Notch in Leukemia

  • Anna C. McCarter
  • Qing Wang
  • Mark ChiangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)


Notch is commonly activated in lymphoid malignancies through ligand-independent and ligand-dependent mechanisms. In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), ligand-independent activation predominates. Negative Regulatory Region (NRR) mutations trigger supraphysiological Notch1 activation by exposing the S2 site to proteolytic cleavage in the absence of ligand. Subsequently, cleavage at the S3 site generates the activated form of Notch, intracellular Notch (ICN). In contrast to T-ALL, in mature lymphoid neoplasms such as chronic lymphocytic leukemia (CLL), the S2 cleavage site is exposed through ligand-receptor interactions. Thus, agents that disrupt ligand-receptor interactions might be useful for treating these malignancies. Notch activation can be enhanced by mutations that delete the C-terminal proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) domain. These mutations do not activate the Notch pathway per se, but rather impair degradation of ICN. In this chapter, we review the mechanisms of Notch activation and the importance of Notch for the genesis and maintenance of lymphoid malignancies. Unfortunately, targeting the Notch pathway with pan-Notch inhibitors in clinical trials has proven challenging. These clinical trials have encountered dose-limiting on-target toxicities and primary resistance. Strategies to overcome these challenges have emerged from the identification and improved understanding of direct oncogenic Notch target genes. Other strategies have arisen from new insights into the “nuclear context” that selectively directs Notch functions in lymphoid cancers. This nuclear context is created by factors that co-bind ICN at cell-type specific transcriptional regulatory elements. Disrupting the functions of these proteins or inhibiting downstream oncogenic pathways might combat cancer without the intolerable side effects of pan-Notch inhibition.


Notch T-cell acute lymphoblastic leukemia Chronic lymphocytic leukemia MYC AKT 



A Disintegrin And Metalloproteinase Domain-Containing Protein 10


ALL1-Fused Gene From Chromosome 4p12 Protein


Angioimmunoblastic T-Cell Lymphomas


AK Mouse Transforming


Acute Megakaryocytic Leukemia


Acute Myeloid Leukemia


Acute Myeloid Leukemia 1


Acute Promyelocytic Leukemia


Anterior Pharynx Defective 1 Homolog A


BCL-2 Binding Component 3


B-Cell CLL/Lymphoma 2


B-Cell CLL/Lymphoma 6


B-Cell CLL/Lymphoma 11B


B-Cell Receptor


Basic Helix-Loop-Helix


B Lymphocyte Kinase


B-cell Linker Protein


Bone Marrow


Bis-2-(5-Phenylacetamido-1,2,4-Thiadiazol-2-Yl)Ethyl Sulfide


Bromodomain Containing 4


Coactivator-associated Arginine Methyltransferase 1


CRISPR Associated Protein 9


Core Binding Factor β


Cyclin C


Cyclin D1


Cyclin D3


Cyclin E1


C-C Chemokine Receptor Type 7


Cyclin-dependent kinase 3


Cyclin-dependent kinase 4


Cyclin-dependent kinase 6


Cyclin-dependent kinase 8


Cyclin-dependent kinase 19


Cyclin Dependent Kinase Inhibitor 1B


Cyclin Dependent Kinase Inhibitor 2D


Chromodomain Helicase DNA Binding Protein 4


Chromatin Immuno-precipitation


Chronic Lymphocytic Leukemia


Complement C3d Receptor 2


Clustered Regularly Interspaced Short Palindromic Repeats


C-X-C Chemokine Receptor Type 4


Ubiquitin Carboxyl-Terminal Hydrolase


DEAD-box RNA Helicase 5


DEP Domain Containing MTOR Interacting Protein


Delta-Like 1


Delta-Like 4


Distal-Less Homeobox 5


Dominant-Negative Mastermind


Deoxyribonucleic Acid


Deltex E3 Ubiquitin Ligase 1


E2A Immunoglobulin Enhancer-Binding Factor E12/E47


Epstein–Barr Nuclear Antigen 2


Epstein–Barr Virus


Eukaryotic Translation Initiation Factor 2A


Extracellular Signal-regulated Kinase


Eight-Twenty One


E26 Avian Leukemia Oncogene 1


Early T-cell Precursor Acute Lymphoblastic Leukemia


F-Box and WD Repeat-Containing Protein 7


Food and Drug Administration


Follicular Lymphoma


Granulocyte-Colony Stimulating Factor


GA Binding Protein Transcription Factor Alpha Subunit


GATA Binding Protein 3


GATA Zinc Finger Domain Containing 2B


Genetically Engineered Mouse Model Of T-ALL






γ-Secretase Inhibitor


Heterodimerization Domain


Histone Deacetylase 1


E2A/Hela E Box-Binding


Hairy And Enhancer Of Split 1


Hematopoietic Stem Cell


Heat Shock Protein 90


Intracellular Notch1


Inhibitor Of DNA Binding 3 HLH Protein


Insulin Like Growth Factor 1 Receptor




Inhibitor Of Kappa-B Kinase


Inhibitor Of Kappa-B Kinase Subunit Alpha


Inhibitor Of Kappa-B Kinase Subunit Beta


Ikaros Family Zinc Finger 1


Interleukin 7 Receptor


Inhibitor of Cyclin-Dependent Kinase 4


Interferon Regulatory Factor 4


Kirsten Rat Sarcoma Viral Oncogene Homolog


Juxtamembrane Extracellular


Ju-nana (Japanese number 17)


Lymphoid Enhancer Binding Factor 1


Leukemia-Initiating Cells


Lim Domain Only 2


Lymph Node


Lin12/Notch Repeats


Leukemia-Associated Non-Coding IGF1R Activator RNA 1


Leukemia Stem Cells


Lysine (K)-Specific Demethylase 1A


Lck/Yes-Related Novel Protein Tyrosine Kinase


Megakaryocytic Acute Leukemia




Mantle Cell Lymphoma


Myeloid Leukemia Cell Differentiation Protein 1


Mechanistic Target Of Rapamycin


Myelocytomatosis proto-oncogene


Notch-MYC enhancer


Notch-dependent MYC enhancer


NF-κB Essential Modulator


Nuclear Factor-κB


Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B Cells 2


Not Otherwise Specified


Negative Regulatory Region


Nucleosome Remodeling Deacetylase


One-Twenty Two


Ribosomal protein S6 kinase beta-1


Polybromo 1


Polybromo-Associated BRG1- Or HBRM-Associated Factors


P300/CBP-Associated Factor


Polymerase Chain Reaction


Patient-Derived Xenograft


Proline (P), Glutamic Acid (E), Serine (S), And Threonine (T)


PHD Finger Protein 8


Phosphatidylinositol 4,5-Bisphosphate 3-Kinase


Protein Inhibitor of Activated STAT


Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta


Phosphatidylinositol (3,4,5)-trisphosphate P3


Phospholipase Cγ


Promyelocytic Leukemia Locus Gene


Protein O-Fucosyltransferase 1


Phosphatase of Regenerating Liver

PTCRA invariant

preTα chain of the pre-T cell receptor


Phosphatase And Tensin Homolog


Quantitative Real Time PCR


Retinoic Acid Receptor-Alpha


Rat Sarcoma virus oncogene


Retinoblastoma Protein


RB Binding Protein 4, Chromatin Remodeling Factor


Recombination Signal Binding Protein For Immunoglobulin Kappa J Region


Relaxed B Proto-Oncogene


Ribonucleic Acid


RNA Polymerase II


Ring Finger Protein 40


Runt Related Transcription Factor 1


MAM-like Stapled Peptides


Sarco/Endoplasmic Reticulum Calcium ATPase


Small Lymphocytic Lymphoma


S-Phase Kinase Associated Protein 2


STIP1 Homology And U-Box Containing Protein 1


Spleen Tyrosine Kinase


T-cell Acute Lymphoblastic Leukemia


T-cell Acute Lymphoblastic Leukemia 1


Transcription Factor 1


T-cell Receptor β


Tumor Protein P53


Tetratricopeptide Repeat


Tribbles Pseudokinase 2


Transcriptional Start Site


Untranslated Region


Zinc Finger Protein C3H Type 36-Like 1


Zinc Finger Protein C3H Type 36-Like 2


Zinc Finger MIZ-Type Containing 1



We thank members of the Maillard and Chiang laboratories for helpful discussions and review of the manuscript. A.M. was supported by the NIH Ruth L. Kirschstein National Research Service Award (F30CA228228), the NIH Cellular and Molecular Biology Training Grant (T32-GM007315), the MSTP Training Grant (T32-GM007863-37), and the Rackham Graduate Student Research Grant. Q.W. and M.C. were supported by the NIH (R01CA196604). M.C. was also supported by the Rally Foundation for Childhood Cancer Research and the Alex’s Lemonade Stand Foundation. The authors apologize to those whose work could not be mentioned owing to space limitations.


  1. Abraham N, Ma MC, Snow JW, Miners MJ, Herndier BG, Goldsmith MA (2005) Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas. Oncogene 24(33):5252–5257. doi:1208726 [pii]. CrossRefPubMedGoogle Scholar
  2. Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F, Satyal S, Gurney A, Hoey T, Seganfreddo E, Basso G, Valtorta S, Moresco RM, Amadori A, Indraccolo S (2014) Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 28(2):278–288. CrossRefPubMedGoogle Scholar
  3. Alcalay M, Meani N, Gelmetti V, Fantozzi A, Fagioli M, Orleth A, Riganelli D, Sebastiani C, Cappelli E, Casciari C, Sciurpi MT, Mariano AR, Minardi SP, Luzi L, Muller H, Di Fiore PP, Frosina G, Pelicci PG (2003) Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest 112(11):1751–1761CrossRefPubMedPubMedCentralGoogle Scholar
  4. Allman D, Karnell FG, Punt JA, Bakkour S, Xu L, Myung PS, Koretzky GA, Pui JC, Aster JC, Pear WS (2001) Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J Exp Med 194(1):99–106CrossRefPubMedPubMedCentralGoogle Scholar
  5. Andersson ER, Lendahl U (2014) Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov 13(5):357–378. CrossRefPubMedGoogle Scholar
  6. Arcaini L, Rossi D, Lucioni M, Nicola M, Bruscaggin A, Fiaccadori V, Riboni R, Ramponi A, Ferretti VV, Cresta S, Casaluci GM, Bonfichi M, Gotti M, Merli M, Maffi A, Arra M, Varettoni M, Rattotti S, Morello L, Guerrera ML, Sciarra R, Gaidano G, Cazzola M, Paulli M (2015) The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection. Haematologica 100(2):246–252. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Armstrong F, Brunet de la Grange P, Gerby B, Rouyez MC, Calvo J, Fontenay M, Boissel N, Dombret H, Baruchel A, Landman-Parker J, Romeo PH, Ballerini P, Pflumio F (2009) NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood 113(8):1730–1740. doi:blood-2008-02-138172 [pii]. CrossRefPubMedGoogle Scholar
  8. Arruga F, Gizdic B, Serra S, Vaisitti T, Ciardullo C, Coscia M, Laurenti L, D'Arena G, Jaksic O, Inghirami G, Rossi D, Gaidano G, Deaglio S (2014) Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia 28(5):1060–1070. CrossRefPubMedGoogle Scholar
  9. Asnafi V, Buzyn A, Le Noir S, Baleydier F, Simon A, Beldjord K, Reman O, Witz F, Fagot T, Tavernier E, Turlure P, Leguay T, Huguet F, Vernant JP, Daniel F, Bene MC, Ifrah N, Thomas X, Dombret H, Macintyre E (2009) NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 113(17):3918–3924. doi:blood-2008-10-184069 [pii]. CrossRefPubMedGoogle Scholar
  10. Aste-Amezaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE (2010) Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One 5(2):e9094. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS (2000) Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by Notch1. Mol Cell Biol 20(20):7505–7515CrossRefPubMedPubMedCentralGoogle Scholar
  12. Aster JC, Pear WS, Blacklow SC (2007) Notch signaling in Leukemia. Annu Rev Pathol 3:587–613CrossRefGoogle Scholar
  13. Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V, Venuta S, Romano MF (2005) Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106(4):1400–1406. CrossRefPubMedGoogle Scholar
  14. Bailey AM, Posakony JW (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9(21):2609–2622CrossRefPubMedGoogle Scholar
  15. Bain G, Maandag EC, Izon DJ, Amsen D, Kruisbeek AM, Weintraub BC, Krop I, Schlissel MS, Feeney AJ, van Roon M et al (1994) E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements [see comments]. Cell 79(5):885–892CrossRefPubMedGoogle Scholar
  16. Bain G, Engel I, Robanus Maandag EC, te Riele HP, Voland JR, Sharp LL, Chun J, Huey B, Pinkel D, Murre C (1997) E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas. Mol Cell Biol 17(8):4782–4791CrossRefPubMedPubMedCentralGoogle Scholar
  17. Balatti V, Bottoni A, Palamarchuk A, Alder H, Rassenti LZ, Kipps TJ, Pekarsky Y, Croce CM (2012) NOTCH1 mutations in CLL associated with trisomy 12. Blood 119(2):329–331. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Baliakas P, Hadzidimitriou A, Sutton LA, Rossi D, Minga E, Villamor N, Larrayoz M, Kminkova J, Agathangelidis A, Davis Z, Tausch E, Stalika E, Kantorova B, Mansouri L, Scarfo L, Cortese D, Navrkalova V, Rose-Zerilli MJ, Smedby KE, Juliusson G, Anagnostopoulos A, Makris AM, Navarro A, Delgado J, Oscier D, Belessi C, Stilgenbauer S, Ghia P, Pospisilova S, Gaidano G, Campo E, Strefford JC, Stamatopoulos K, Rosenquist R, European Research Initiative on CLL (2015) Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 29(2):329–336. CrossRefPubMedGoogle Scholar
  19. Barata JT, Keenan TD, Silva A, Nadler LM, Boussiotis VA, Cardoso AA (2004) Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia. Haematologica 89(12):1459–1467PubMedGoogle Scholar
  20. Barton K, Muthusamy N, Fischer C, Ting CN, Walunas TL, Lanier LL, Leiden JM (1998) The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity 9(4):555–563. doi:S1074-7613(00)80638-X [pii]CrossRefPubMedGoogle Scholar
  21. Bea S, Valdes-Mas R, Navarro A, Salaverria I, Martin-Garcia D, Jares P, Gine E, Pinyol M, Royo C, Nadeu F, Conde L, Juan M, Clot G, Vizan P, Di Croce L, Puente DA, Lopez-Guerra M, Moros A, Roue G, Aymerich M, Villamor N, Colomo L, Martinez A, Valera A, Martin-Subero JI, Amador V, Hernandez L, Rozman M, Enjuanes A, Forcada P, Muntanola A, Hartmann EM, Calasanz MJ, Rosenwald A, Ott G, Hernandez-Rivas JM, Klapper W, Siebert R, Wiestner A, Wilson WH, Colomer D, Lopez-Guillermo A, Lopez-Otin C, Puente XS, Campo E (2013) Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A 110(45):18250–18255. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A, Screpanti I (2000) Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J 19(13):3337–3348CrossRefPubMedPubMedCentralGoogle Scholar
  23. Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling HJ, Hayday AC, Frati L, von Boehmer H, Gulino A, Screpanti I (2002) Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A 99(6):3788–3793CrossRefPubMedPubMedCentralGoogle Scholar
  24. Bellavia D, Mecarozzi M, Campese AF, Grazioli P, Talora C, Frati L, Gulino A, Screpanti I (2007) Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. EMBO J 26(6):1670–1680. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, Capodieci P, Deplazes-Lauber J, Petropoulos K, Thiel P, Ponsel D, Hee Choi S, LeMotte P, London A, Goetcshkes M, Nolin E, Jones MD, Slocum K, Kluk MJ, Weinstock DM, Christodoulou A, Weinberg O, Jaehrling J, Ettenberg SA, Buckler A, Blacklow SC, Aster JC, Fryer CJ (2016) Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35(47):6077–6086. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Beverly LJ, Capobianco AJ (2003) Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell 3(6):551–564CrossRefPubMedGoogle Scholar
  27. Beverly LJ, Felsher DW, Capobianco AJ (2005) Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. Cancer Res 65(16):7159–7168. doi:65/16/7159[pii]. CrossRefPubMedGoogle Scholar
  28. Bonnet M, Loosveld M, Montpellier B, Navarro JM, Quilichini B, Picard C, Di Cristofaro J, Bagnis C, Fossat C, Hernandez L, Mamessier E, Roulland S, Morgado E, Formisano-Treziny C, Dik WA, Langerak AW, Prebet T, Vey N, Michel G, Gabert J, Soulier J, Macintyre EA, Asnafi V, Payet-Bornet D, Nadel B (2011) Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia. Blood 117(24):6650–6659. CrossRefPubMedGoogle Scholar
  29. Borggrefe T, Liefke R (2012) Fine-tuning of the intracellular canonical Notch signaling pathway. Cell Cycle 11(2):264–276. CrossRefPubMedGoogle Scholar
  30. Bories JC, Willerford DM, Grevin D, Davidson L, Camus A, Martin P, Stehelin D, Alt FW (1995) Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature 377(6550):635–638. CrossRefPubMedGoogle Scholar
  31. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol.
  32. Bretones G, Delgado MD, Leon J (2015) Myc and cell cycle control. Biochim Biophys Acta 1849(5):506–516. CrossRefPubMedGoogle Scholar
  33. Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG, Klinakis A, Lukyanov Y, Tseng JC, Sen F, Gehrie E, Li M, Newcomb E, Zavadil J, Meruelo D, Lipp M, Ibrahim S, Efstratiadis A, Zagzag D, Bromberg JS, Dustin ML, Aifantis I (2009) CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459(7249):1000–1004. doi:nature08020 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Campese AF, Garbe AI, Zhang F, Grassi F, Screpanti I, von Boehmer H (2006) Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood 108(1):305–310. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Carlesso N, Aster JC, Sklar J, Scadden DT (1999) Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood 93(3):838–848PubMedGoogle Scholar
  36. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ (2007) Notch signals positively regulate activity of the mTOR pathway in T cell acute lymphoblastic leukemia. Blood 110(1):278–286CrossRefPubMedPubMedCentralGoogle Scholar
  37. Chari S, Winandy S (2008) Ikaros regulates Notch target gene expression in developing thymocytes. J Immunol 181(9):6265–6274. doi:181/9/6265 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  38. Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC (2006) Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Mol Cell Biol 26(16):6261–6271CrossRefPubMedPubMedCentralGoogle Scholar
  39. Chiang MY, Xu L, Shestova O, Histen G, L’Heureux S, Romany C, Childs ME, Gimotty PA, Aster JC, Pear WS (2008) Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Investig 118(9):14CrossRefGoogle Scholar
  40. Chiang MY, Shestova O, Xu L, Aster JC, Pear WS (2013) Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood 121(6):905–917. blood-2012-03-416503 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  41. Chiang MY, Wang Q, Gormley AC, Stein SJ, Xu L, Shestova O, Aster JC, Pear WS (2016) High selective pressure for Notch1 mutations that induce Myc in T cell acute lymphoblastic leukemia. Blood.
  42. Chiarini F, Fala F, Tazzari PL, Ricci F, Astolfi A, Pession A, Pagliaro P, McCubrey JA, Martelli AM (2009) Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 69(8):3520–3528. CrossRefPubMedGoogle Scholar
  43. Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P (2012) The requirement for cyclin D function in tumor maintenance. Cancer Cell 22(4):438–451. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Chung J, Ebens CL, Perkey E, Radojcic V, Koch U, Scarpellino L, Tong A, Allen F, Wood S, Feng J, Friedman A, Granadier D, Tran IT, Chai Q, Onder L, Yan M, Reddy P, Blazar BR, Huang AY, Brennan TV, Bishop DK, Ludewig B, Siebel CW, Radtke F, Luther SA, Maillard I (2017) Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands. J Clin Invest.
  45. Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H (2010) NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 24 (12):2023-2031. leu2010205 [pii]
  46. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D (2009) Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10(2):147–156. doi:S1470-2045(08)70314-0 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Cullion K, Draheim KM, Hermance N, Tammam J, Sharma VM, Ware C, Nikov G, Krishnamoorthy V, Majumder PK, Kelliher MA (2009) Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 113(24):6172–6181. doi:blood-2008-02-136762 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Dai TY, Cao L, Yang ZC, Li YS, Tan L, Ran XZ, Shi CM (2014) P68 RNA helicase as a molecular target for cancer therapy. J Exp Clin Cancer Res 33:64. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Dail M, Li Q, McDaniel A, Wong J, Akagi K, Huang B, Kang HC, Kogan SC, Shokat K, Wolff L, Braun BS, Shannon K (2010) Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents. Proc Natl Acad Sci U S A 107(11):5106–5111. CrossRefPubMedPubMedCentralGoogle Scholar
  50. de Pooter RF, Schmitt TM, de la Pompa JL, Fujiwara Y, Orkin SH, Zuniga-Pflucker JC (2006) Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors. J Immunol 176(9):5267–5275CrossRefPubMedGoogle Scholar
  51. Deangelo DJ, Stone RM, Silverman LB, Stock W, Attar EC, Fearen I, Dallob A, Matthews C, Stone J, Freedman SJ, Aster J (2009) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol., 2006 ASCO Annual Meeting Proceedings Part I 24 (18S (June 20 Supplement)):6585Google Scholar
  52. Deftos ML, He YW, Ojala EW, Bevan MJ (1998) Correlating notch signaling with thymocyte maturation. Immunity 9(6):777–786CrossRefPubMedPubMedCentralGoogle Scholar
  53. Deftos ML, Huang E, Ojala EW, Forbush KA, Bevan MJ (2000) Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13(1):73–84CrossRefPubMedPubMedCentralGoogle Scholar
  54. Demarest RM, Dahmane N, Capobianco AJ (2011) Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia. Blood 117(10):2901–2909. doi:blood-2010-05-286351 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Depew MJ, Liu JK, Long JE, Presley R, Meneses JJ, Pedersen RA, Rubenstein JL (1999) Dlx5 regulates regional development of the branchial arches and sensory capsules. Development 126(17):3831–3846PubMedGoogle Scholar
  56. Di Ianni M, Baldoni S, Rosati E, Ciurnelli R, Cavalli L, Martelli MF, Marconi P, Screpanti I, Falzetti F (2009) A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol 146(6):689–691. CrossRefPubMedGoogle Scholar
  57. Dohda T, Maljukova A, Liu L, Heyman M, Grander D, Brodin D, Sangfelt O, Lendahl U (2007) Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines. Exp Cell Res 313(14):3141–3152. CrossRefPubMedGoogle Scholar
  58. Dong Y, Zhang L, Zhang S, Bai Y, Chen H, Sun X, Yong W, Li W, Colvin SC, Rhodes SJ, Shou W, Zhang ZY (2012) Phosphatase of regenerating liver 2 (PRL2) is essential for placental development by down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and activating Akt protein. J Biol Chem 287(38):32172–32179. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Dong Y, Zhang L, Bai Y, Zhou HM, Campbell AM, Chen H, Yong W, Zhang W, Zeng Q, Shou W, Zhang ZY (2014) Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis. J Biol Chem 289(6):3799–3810. CrossRefPubMedGoogle Scholar
  60. Dudley DD, Wang HC, Sun XH (2009) Hes1 potentiates T cell lymphomagenesis by up-regulating a subset of notch target genes. PLoS One 4(8):e6678. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Dumortier A, Durham AD, Di Piazza M, Vauclair S, Koch U, Ferrand G, Ferrero I, Demehri S, Song LL, Farr AG, Leonard WJ, Kopan R, Miele L, Hohl D, Finke D, Radtke F (2010) Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS One 5(2):e9258. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Egawa T, Tillman RE, Naoe Y, Taniuchi I, Littman DR (2007) The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med 204(8):1945–1957. doi:jem.20070133 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Eguchi-Ishimae M, Eguchi M, Kempski H, Greaves M (2008) NOTCH1 mutation can be an early, prenatal genetic event in T-ALL. Blood 111 (1):376-378Google Scholar
  64. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4):649–661CrossRefPubMedGoogle Scholar
  65. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435 (7044):959-963. doi:nature03659 [pii]
  66. Espinosa L, Cathelin S, D'Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Ingles-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Abdel-Wahab O, Kucine N, Sun SC, Song G, Mullighan CC, Levine RL, Rajewsky K, Aifantis I, Bigas A (2010) The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 18(3):268–281. doi:S1535-6108(10)00302-8 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, Grunn A, Fangazio M, Capello D, Monti S, Cresta S, Gargiulo E, Forconi F, Guarini A, Arcaini L, Paulli M, Laurenti L, Larocca LM, Marasca R, Gattei V, Oscier D, Bertoni F, Mullighan CG, Foa R, Pasqualucci L, Rabadan R, Dalla-Favera R, Gaidano G (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 208(7):1389–1401. jem.20110921 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  68. Fabbri G, Holmes AB, Viganotti M, Scuoppo C, Belver L, Herranz D, Yan XJ, Kieso Y, Rossi D, Gaidano G, Chiorazzi N, Ferrando AA, Dalla-Favera R (2017) Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A.
  69. Fasnacht N, Huang HY, Koch U, Favre S, Auderset F, Chai Q, Onder L, Kallert S, Pinschewer DD, MacDonald HR, Tacchini-Cottier F, Ludewig B, Luther SA, Radtke F (2014) Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J Exp Med 211(11):2265–2279. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Felsher DW, Bishop JM (1999) Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4(2):199–207CrossRefPubMedGoogle Scholar
  71. Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16(4):509–520CrossRefPubMedGoogle Scholar
  72. Garcia-Ojeda ME, Klein Wolterink RG, Lemaitre F, Richard-Le Goff O, Hasan M, Hendriks RW, Cumano A, Di Santo JP (2013) GATA-3 promotes T-cell specification by repressing B-cell potential in pro-T cells in mice. Blood 121(10):1749–1759. CrossRefPubMedGoogle Scholar
  73. Geimer Le Lay AS, Oravecz A, Mastio J, Jung C, Marchal P, Ebel C, Dembele D, Jost B, Le Gras S, Thibault C, Borggrefe T, Kastner P, Chan S (2014) The tumor suppressor ikaros shapes the repertoire of notch target genes in T cells. Sci Signal 7(317). [pii]
  74. Gonzalez-Garcia S, Garcia-Peydro M, Martin-Gayo E, Ballestar E, Esteller M, Bornstein R, de la Pompa JL, Ferrando AA, Toribio ML (2009) CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia. J Exp Med 206 (4):779-791. doi:jem.20081922 [pii]
  75. Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC (2007) Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14(4):295–300CrossRefPubMedGoogle Scholar
  76. Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR, Aster JC, Blacklow SC (2009) Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood 113(18):4381–4390. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Grieselhuber NR, Klco JM, Verdoni AM, Lamprecht T, Sarkaria SM, Wartman LD, Ley TJ (2013) Notch signaling in acute promyelocytic leukemia. Leukemia 27(7):1548–1557. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, Dahlberg S, Neuberg D, Moreau LA, Winter SS, Larson R, Zhang J, Protopopov A, Chin L, Pandolfi PP, Silverman LB, Hunger SP, Sallan SE, Look AT (2009) High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114(3):647–650. doi:blood-2009-02-206722 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Gutierrez A, Pan L, Groen RW, Baleydier F, Kentsis A, Marineau J, Grebliunaite R, Kozakewich E, Reed C, Pflumio F, Poglio S, Uzan B, Clemons P, VerPlank L, An F, Burbank J, Norton S, Tolliday N, Steen H, Weng AP, Yuan H, Bradner JE, Mitsiades C, Look AT, Aster JC (2014) Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 124(2):644–655. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Hattori N, Kawamoto H, Fujimoto S, Kuno K, Katsura Y (1996) Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus. J Exp Med 184(3):1137–1147CrossRefPubMedGoogle Scholar
  81. Helbig C, Amsen D (2015) Notch Signaling: Piercing a Harness of Simplicity. Immunity 43(5):831–833. CrossRefPubMedGoogle Scholar
  82. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navas D, Cordon-Cardo C, Clappier E, Soulier J, Ferrando AA (2014) A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med 20(10):1130–1137. nm.3665 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  83. Herranz D, Ambesi-Impiombato A, Sudderth J, Sanchez-Martin M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, Marquez J, Mates JM, Kung AL, Rayport S, Cordon-Cardo C, DeBerardinis RJ, Ferrando AA (2015) Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med 21(10):1182–1189. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Hodson DJ, Janas ML, Galloway A, Bell SE, Andrews S, Li CM, Pannell R, Siebel CW, MacDonald HR, De Keersmaecker K, Ferrando AA, Grutz G, Turner M (2010) Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nat Immunol 11(8):717–724. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Hosoya T, Kuroha T, Moriguchi T, Cummings D, Maillard I, Lim KC, Engel JD (2009) GATA-3 is required for early T lineage progenitor development. J Exp Med 206(13):2987–3000. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, Ando K, Zuklys S, Hollander GA, Shima DT, Habu S (2008) Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 205(11):2507–2513. CrossRefPubMedPubMedCentralGoogle Scholar
  87. Hu Y, Su H, Liu C, Wang Z, Huang L, Wang Q, Liu S, Chen S, Zhou J, Li P, Chen Z, Liu H, Qing G (2016) DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia. Oncogene.
  88. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471(7336):104–109. nature09732 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  89. Jenkinson S, Koo K, Mansour MR, Goulden N, Vora A, Mitchell C, Wade R, Richards S, Hancock J, Moorman AV, Linch DC, Gale RE (2013) Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. Leukemia 27(1):41–47. leu2012176 [pii]CrossRefPubMedGoogle Scholar
  90. Jeromin S, Weissmann S, Haferlach C, Dicker F, Bayer K, Grossmann V, Alpermann T, Roller A, Kohlmann A, Haferlach T, Kern W, Schnittger S (2014) SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 28(1):108–117. CrossRefPubMedGoogle Scholar
  91. Jitschin R, Braun M, Qorraj M, Saul D, Le Blanc K, Zenz T, Mougiakakos D (2015) Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling. Blood 125(22):3432–3436. CrossRefPubMedGoogle Scholar
  92. Johnson K, Hashimshony T, Sawai CM, Pongubala JM, Skok JA, Aifantis I, Singh H (2008) Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity 28(3):335–345. doi:S1074-7613(08)00044-7 [pii]. CrossRefPubMedGoogle Scholar
  93. Joshi I, Minter LM, Telfer J, Demarest RM, Capobianco AJ, Aster JC, Sicinski P, Fauq A, Golde TE, Osborne BA (2009) Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 113(8):1689–1698. doi:blood-2008-03-147967 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Jung C, Mittler G, Oswald F, Borggrefe T (2013) RNA helicase Ddx5 and the noncoding RNA SRA act as coactivators in the Notch signaling pathway. Biochim Biophys Acta 1833(5):1180–1189. CrossRefPubMedGoogle Scholar
  95. Kannan S, Sutphin RM, Hall MG, Golfman LS, Fang W, Nolo RM, Akers LJ, Hammitt RA, McMurray JS, Kornblau SM, Melnick AM, Figueroa ME, Zweidler-McKay PA (2013) Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med 210(2):321–337. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Karube K, Martinez D, Royo C, Navarro A, Pinyol M, Cazorla M, Castillo P, Valera A, Carrio A, Costa D, Colomer D, Rosenwald A, Ott G, Esteban D, Gine E, Lopez-Guillermo A, Campo E (2014) Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours. J Pathol 234(3):423–430. CrossRefPubMedGoogle Scholar
  97. Kathrein KL, Chari S, Winandy S (2008) Ikaros directly represses the notch target gene Hes1 in a leukemia T cell line: implications for CD4 regulation. J Biol Chem 283(16):10476–10484. doi:M709643200 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG, Chiang MY, Huebner-Chan DR, Bailey NG, Yang DT, Bhagat G, Miranda RN, Bahler DW, Medeiros LJ, Lim MS, Elenitoba-Johnson KS (2012) Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med 209(9):1553–1565. jem.20120910 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  99. King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, Aranda-Orgilles B, Perez-Garcia A, Shi J, Vakoc C, Sandy P, Shen SS, Ferrando A, Aifantis I (2013) The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability. Cell 153(7):1552–1566. S0092-8674(13)00647-8 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  100. Kleinmann E, Geimer Le Lay AS, Sellars M, Kastner P, Chan S (2008) Ikaros represses the transcriptional response to Notch signaling in T-cell development. Mol Cell Biol 28(24):7465–7475. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, van De Walle I, Cathelin S, Trimarchi T, Araldi E, Liu C, Ibrahim S, Beran M, Zavadil J, Efstratiadis A, Taghon T, Michor F, Levine RL, Aifantis I (2011) A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473(7346):230–233. doi:nature09999 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Kluk MJ, Ashworth T, Wang H, Knoechel B, Mason EF, Morgan EA, Dorfman D, Pinkus G, Weigert O, Hornick JL, Chirieac LR, Hirsch M, Oh DJ, South AP, Leigh IM, Pourreyron C, Cassidy AJ, Deangelo DJ, Weinstock DM, Krop IE, Dillon D, Brock JE, Lazar AJ, Peto M, Cho RJ, Stoeck A, Haines BB, Sathayanrayanan S, Rodig S, Aster JC (2013) Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry. PLoS One 8(6):e67306. PONE-D-13-13213 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  103. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46(4):364–370. ng.2913 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  104. Knoechel B, Bhattt A, DeAngelo DJ, Aster JC (2015) Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case. Cold Spring Harb Mol Case Stud 1(1):a000539CrossRefPubMedPubMedCentralGoogle Scholar
  105. Kobayashi M, Bai Y, Chen S, Gao R, Yao C, Cai W, Cardoso AA, Croop J, Zhang ZY, Liu Y (2016) Phosphatase PRL2 promotes oncogenic NOTCH1-induced T cell leukemia. Leukemia.
  106. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, Pierres M, Manley NR, Duarte A, Macdonald HR, Radtke F (2008) Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 205(11):2515–2523. doi:jem.20080829 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, Elledge SJ (2001) Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294(5540):173–177CrossRefPubMedGoogle Scholar
  108. Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD, Koehler R, Tolle G, Bandapalli OR, Breit S, Muckenthaler MU, Kulozik AE (2010) The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia 24(12):2005–2013. leu2010203 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  109. Kridel R, Meissner B, Rogic S, Boyle M, Telenius A, Woolcock B, Gunawardana J, Jenkins C, Cochrane C, Ben-Neriah S, Tan K, Morin RD, Opat S, Sehn LH, Connors JM, Marra MA, Weng AP, Steidl C, Gascoyne RD (2012) Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119(9):1963–1971. blood-2011-11-391474 [pii]CrossRefPubMedGoogle Scholar
  110. Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, Butowski N, Groves MD, Kesari S, Freedman SJ, Blackman S, Watters J, Loboda A, Podtelezhnikov A, Lunceford J, Chen C, Giannotti M, Hing J, Beckman R, Lorusso P (2012) Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 30(19):2307–2313. CrossRefPubMedGoogle Scholar
  111. Krysiak K, Gomez F, White BS, Matlock M, Miller CA, Trani L, Fronick CC, Fulton RS, Kreisel F, Cashen AF, Carson KR, Berrien-Elliott MM, Bartlett NL, Griffith M, Griffith OL, Fehniger TA (2016) Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood.
  112. La Starza R, Borga C, Barba G, Pierini V, Schwab C, Matteucci C, Lema Fernandez AG, Leszl A, Cazzaniga G, Chiaretti S, Basso G, Harrison CJ, Te Kronnie G, Mecucci C (2014) Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations. Blood 124(24):3577–3582. CrossRefPubMedGoogle Scholar
  113. Lange BJ, Raimondi SC, Heerema N, Nowell PC, Minowada J, Steinherz PE, Arenson EB, O'Connor R, Santoli D (1992) Pediatric leukemia/lymphoma with t(8;14)(q24;q11). Leukemia 6(7):613–618PubMedGoogle Scholar
  114. Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, Lin S, Prochownik E, Trede NS, Zon LI, Look AT (2003) Myc-induced T cell leukemia in transgenic zebrafish. Science 299(5608):887–890CrossRefPubMedGoogle Scholar
  115. Larrayoz M, Rose-Zerilli MJ, Kadalayil L, Parker H, Blakemore S, Forster J, Davis Z, Steele AJ, Collins A, Else M, Catovsky D, Oscier DG, Strefford JC (2016) Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial. Leukemia.
  116. Li X, Gounari F, Protopopov A, Khazaie K, von Boehmer H (2008) Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. J Exp Med 205 (12):2851-2861. doi:jem.20081561 [pii]
  117. Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, Liu L, Wang H, King B, Shaik S, Gutierrez A, Ordureau A, Otto T, Kreslavsky T, Baitsch L, Bury L, Meyer CA, Ke N, Mulry KA, Kluk MJ, Roy M, Kim S, Zhang X, Geng Y, Zagozdzon A, Jenkinson S, Gale RE, Linch DC, Zhao JJ, Mullighan CG, Harper JW, Aster JC, Aifantis I, von Boehmer H, Gygi SP, Wei W, Look AT, Sicinski P (2014) Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 16(11):1080–1091. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Lin S, Tian L, Shen H, Gu Y, Li JL, Chen Z, Sun X, You MJ, Wu L (2013) DDX5 is a positive regulator of oncogenic NOTCH1 signaling in T cell acute lymphoblastic leukemia. Oncogene 32(40):4845–4853. CrossRefPubMedGoogle Scholar
  119. Liu H, Chi AW, Arnett KL, Chiang MY, Xu L, Shestova O, Wang H, Li YM, Bhandoola A, Aster JC, Blacklow SC, Pear WS (2010) Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 24(21):2395–2407. doi:gad.1975210 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, McCastlain K, Edmonson M, Pounds SB, Shi L, Zhou X, Ma X, Sioson E, Li Y, Rusch M, Gupta P, Pei D, Cheng C, Smith MA, Auvil JG, Gerhard DS, Relling MV, Winick NJ, Carroll AJ, Heerema NA, Raetz E, Devidas M, Willman CL, Harvey RC, Carroll WL, Dunsmore KP, Winter SS, Wood BL, Sorrentino BP, Downing JR, Loh ML, Hunger SP, Zhang J, Mullighan CG (2017) The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 49(8):1211–1218. CrossRefPubMedPubMedCentralGoogle Scholar
  121. Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, Araldi E, Hu W, Freund J, Abdel-Wahab O, Ibrahim S, Skokos D, Armstrong SA, Levine RL, Park CY, Aifantis I (2013) Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 210(2):301–319. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernandez-Lemus E, Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR (2012) Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 109(10):3879–3884. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Loosveld M, Castellano R, Gon S, Goubard A, Crouzet T, Pouyet L, Prebet T, Vey N, Nadel B, Collette Y, Payet-Bornet D (2014) Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL. Oncotarget 5(10):3168–3172. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML, Aster JC, Blacklow SC (2006) Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol 26(12):4642–4651CrossRefPubMedPubMedCentralGoogle Scholar
  125. Mansour MR, Duke V, Foroni L, Patel B, Allen CG, Ancliff PJ, Gale RE, Linch DC (2007) Notch-1 mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia. Clin Cancer Res 13(23):6964–6969CrossRefPubMedGoogle Scholar
  126. Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K, Allen CG, Gale RE, Buck G, Richards S, Paietta E, Rowe JM, Tallman MS, Goldstone AH, Ferrando AA, Linch DC (2009) Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol 27(26):4352–4356. JCO.2009.22.0996 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  127. Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, Balmain A (2008) FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 321(5895):1499–1502. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  128. Marcais A, Jeannet R, Hernandez L, Soulier J, Sigaux F, Chan S, Kastner P (2010) Genetic inactivation of Ikaros is a rare event in human T-ALL. Leuk Res 34(4):426–429. doi:S0145-2126(09)00472-X [pii]. CrossRefPubMedGoogle Scholar
  129. Margolin AA, Palomero T, Sumazin P, Califano A, Ferrando AA, Stolovitzky G (2009) ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes. Proc Natl Acad Sci U S A 106(1):244–249. [pii]CrossRefPubMedGoogle Scholar
  130. Martinez D, Navarro A, Martinez-Trillos A, Molina-Urra R, Gonzalez-Farre B, Salaverria I, Nadeu F, Enjuanes A, Clot G, Costa D, Carrio A, Villamor N, Colomer D, Martinez A, Bens S, Siebert R, Wotherspoon A, Bea S, Matutes E, Campo E (2016) NOTCH1, TP53, and MAP2K1 Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease. Am J Surg Pathol 40(2):192–201. CrossRefPubMedGoogle Scholar
  131. McMillan BJ, Zimmerman B, Egan ED, Lofgren M, Xu X, Hesser A, Blacklow SC (2017) Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations. Glycobiology:1–10.
  132. Medyouf H, Gao X, Armstrong F, Gusscott S, Liu Q, Gedman AL, Matherly LH, Schultz KR, Pflumio F, You MJ, Weng AP (2010) Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss. Blood 115(6):1175–1184. doi:blood-2009-04-214718 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Medyouf H, Gusscott S, Wang H, Tseng JC, Wai C, Nemirovsky O, Trumpp A, Pflumio F, Carboni J, Gottardis M, Pollak M, Kung AL, Aster JC, Holzenberger M, Weng AP (2011) High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. J Exp Med 208(9):1809–1822. doi:jem.20110121 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Mendes RD, Sarmento LM, Cante-Barrett K, Zuurbier L, Buijs-Gladdines JG, Povoa V, Smits WK, Abecasis M, Yunes JA, Sonneveld E, Horstmann MA, Pieters R, Barata JT, Meijerink JP (2014) PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 124(4):567–578. CrossRefPubMedGoogle Scholar
  135. Mendes RD, Cante-Barrett K, Pieters R, Meijerink JP (2016) The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia. Haematologica 101(9):1010–1017. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Mercher T, Raffel GD, Moore SA, Cornejo MG, Baudry-Bluteau D, Cagnard N, Jesneck JL, Pikman Y, Cullen D, Williams IR, Akashi K, Shigematsu H, Bourquin JP, Giovannini M, Vainchenker W, Levine RL, Lee BH, Bernard OA, Gilliland DG (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 119(4):852–864. doi:35901 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, Greenberg B, Ciaccio PJ (2004) Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82(1):341–358. CrossRefPubMedGoogle Scholar
  138. Minervini A, Minervini CF, Anelli L, Zagaria A, Casieri P, Coccaro N, Cumbo C, Tota G, Impera L, Orsini P, Brunetti C, Giordano A, Specchia G, Albano F (2016) Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia. Oncotarget.
  139. Minuzzo S, Agnusdei V, Pusceddu I, Pinazza M, Moserle L, Masiero M, Rossi E, Crescenzi M, Hoey T, Ponzoni M, Amadori A, Indraccolo S (2015) DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice. Carcinogenesis 36(1):115–121. CrossRefPubMedGoogle Scholar
  140. Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462 (7270):182-188. doi:nature08543 [pii]
  141. Muthusamy N, Barton K, Leiden JM (1995) Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377(6550):639–642. CrossRefPubMedGoogle Scholar
  142. Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M, Jares P, Navarro A, Martin-Garcia D, Bea S, Salaverria I, Oldreive C, Aymerich M, Suarez-Cisneros H, Rozman M, Villamor N, Colomer D, Lopez-Guillermo A, Gonzalez M, Alcoceba M, Terol MJ, Colado E, Puente XS, Lopez-Otin C, Enjuanes A, Campo E (2016) Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 127(17):2122–2130. CrossRefPubMedPubMedCentralGoogle Scholar
  143. Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC (2007) Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc Natl Acad Sci U S A 104(7):2103–2108. doi:0611092104 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  144. Neumann M, Heesch S, Schlee C, Schwartz S, Gokbuget N, Hoelzer D, Konstandin NP, Ksienzyk B, Vosberg S, Graf A, Krebs S, Blum H, Raff T, Bruggemann M, Hofmann WK, Hecht J, Bohlander SK, Greif PA, Baldus CD (2013) Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 121(23):4749–4752. CrossRefPubMedGoogle Scholar
  145. Nie L, Xu M, Vladimirova A, Sun XH (2003) Notch-induced E2A ubiquitination and degradation are controlled by MAP kinase activities. EMBO J 22(21):5780–5792CrossRefPubMedPubMedCentralGoogle Scholar
  146. Nowell CS, Radtke F (2017) Notch as a tumour suppressor. Nat Rev Cancer 17(3):145–159. CrossRefPubMedGoogle Scholar
  147. Ohtani Y, Xu S, Petrovic J, Xu L, Aster JC, Pear WS (2015) Modular domains within a super enhancer determine drug resistance in leukemia. Blood (ASH Annual Meeting Abstracts) 126(23):44Google Scholar
  148. Onaindia A, Gomez S, Piris-Villaespesa M, Martinez-Laperche C, Cereceda L, Montes-Moreno S, Batlle A, de Villambrosia SG, Pollan M, Martin-Acosta P, Gonzalez-Rincon J, Menarguez J, Alves J, Rodriguez-Pinilla SM, Garcia JF, Mollejo M, Fraga M, Garcia-Marco JA, Piris MA, Sanchez-Beato M (2015) Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation. Haematologica 100(5):e200–e203. CrossRefPubMedPubMedCentralGoogle Scholar
  149. O’Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, Alt FW, Kelliher M, Look AT (2006) Activating Notch1 mutations in mouse models of T-ALL. Blood 107(2):781–785CrossRefPubMedPubMedCentralGoogle Scholar
  150. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, Hardwick J, Welcker M, Meijerink JP, Pieters R, Draetta G, Sears R, Clurman BE, Look AT (2007a) FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors. J Exp Med 204(8):1813–1824CrossRefPubMedPubMedCentralGoogle Scholar
  151. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, Hardwick J, Welcker M, Meijerink JP, Pieters R, Draetta G, Sears R, Clurman BE, Look AT (2007b) FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 204(8):1813–1824CrossRefPubMedPubMedCentralGoogle Scholar
  152. Palii CG, Perez-Iratxeta C, Yao Z, Cao Y, Dai F, Davison J, Atkins H, Allan D, Dilworth FJ, Gentleman R, Tapscott SJ, Brand M (2011) Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages. EMBO J 30(3):494–509. CrossRefPubMedGoogle Scholar
  153. Palomero T, Barnes KC, Real PJ, Glade Bender JL, Sulis ML, Murty VV, Colovai AI, Balbin M, Ferrando AA (2006a) CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 20(7):1279–1287. CrossRefPubMedGoogle Scholar
  154. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA (2006b) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 103(48):18261–18266CrossRefPubMedPubMedCentralGoogle Scholar
  155. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zuniga-Pflucker JC, Dominguez M, Ferrando AA (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13(10):1203–1210CrossRefPubMedPubMedCentralGoogle Scholar
  156. Pancewicz J, Taylor JM, Datta A, Baydoun HH, Waldmann TA, Hermine O, Nicot C (2010) Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. Proc Natl Acad Sci U S A 107(38):16619–16624. CrossRefPubMedPubMedCentralGoogle Scholar
  157. Papayannidis C, DeAngelo DJ, Stock W, Huang B, Shaik MN, Cesari R, Zheng X, Reynolds JM, English PA, Ozeck M, Aster JC, Kuo F, Huang D, Lira PD, McLachlan KR, Kern KA, Garcia-Manero G, Martinelli G (2015) A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J 5:e350. CrossRefPubMedPubMedCentralGoogle Scholar
  158. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, Baltimore D (1996) Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 183(5):2283–2291CrossRefPubMedGoogle Scholar
  159. Pikman Y, Alexe G, Roti G, Saur Conway A, Furman A, Lee ES, Place AE, Kim S, Saran C, Modiste R, Weinstock DM, Harris M, Kung AL, Silverman LB, Stegmaier K (2016) Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia. Clin Cancer Res.
  160. Pillai S, Cariappa A (2009) The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol 9(11):767–777. CrossRefPubMedGoogle Scholar
  161. Pinnell N, Yan R, Cho HJ, Keeley T, Murai MJ, Liu Y, Alarcon AS, Qin J, Wang Q, Kuick R, Elenitoba-Johnson KS, Maillard I, Samuelson LC, Cierpicki T, Chiang MY (2015) The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia. Immunity 43(5):870–883. CrossRefPubMedPubMedCentralGoogle Scholar
  162. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, Sanchez-Martin M, Perez-Garcia A, Rigo I, Castillo M, Indraccolo S, Cross JR, de Stanchina E, Paietta E, Racevskis J, Rowe JM, Tallman MS, Basso G, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA (2013) Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 24(6):766–776. CrossRefPubMedGoogle Scholar
  163. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea S, Gonzalez-Diaz M, Bassaganyas L, Baumann T, Juan M, Lopez-Guerra M, Colomer D, Tubio JM, Lopez C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernandez JM, Puente DA, Freije JM, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes A, Hernandez L, Yague J, Nicolas P, Romeo-Casabona CM, Himmelbauer H, Castillo E, Dohm JC, de Sanjose S, Piris MA, de Alava E, San Miguel J, Royo R, Gelpi JL, Torrents D, Orozco M, Pisano DG, Valencia A, Guigo R, Bayes M, Heath S, Gut M, Klatt P, Marshall J, Raine K, Stebbings LA, Futreal PA, Stratton MR, Campbell PJ, Gut I, Lopez-Guillermo A, Estivill X, Montserrat E, Lopez-Otin C, Campo E (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475(7354):101–105. CrossRefPubMedPubMedCentralGoogle Scholar
  164. Puente XS, Bea S, Valdes-Mas R, Villamor N, Gutierrez-Abril J, Martin-Subero JI, Munar M, Rubio-Perez C, Jares P, Aymerich M, Baumann T, Beekman R, Belver L, Carrio A, Castellano G, Clot G, Colado E, Colomer D, Costa D, Delgado J, Enjuanes A, Estivill X, Ferrando AA, Gelpi JL, Gonzalez B, Gonzalez S, Gonzalez M, Gut M, Hernandez-Rivas JM, Lopez-Guerra M, Martin-Garcia D, Navarro A, Nicolas P, Orozco M, Payer AR, Pinyol M, Pisano DG, Puente DA, Queiros AC, Quesada V, Romeo-Casabona CM, Royo C, Royo R, Rozman M, Russinol N, Salaverria I, Stamatopoulos K, Stunnenberg HG, Tamborero D, Terol MJ, Valencia A, Lopez-Bigas N, Torrents D, Gut I, Lopez-Guillermo A, Lopez-Otin C, Campo E (2015) Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526(7574):519–524. CrossRefPubMedGoogle Scholar
  165. Qian L, Zhang W, Lei B, He A, Ye L, Li X, Dong X (2016) MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1. Oncol Rep.
  166. Rakowski LA, Lehotzky EA, Chiang MY (2011) Transient Responses to NOTCH and TLX1/HOX11 Inhibition in T-Cell Acute Lymphoblastic Leukemia/Lymphoma. PLoS One 6(2):e16761. CrossRefPubMedPubMedCentralGoogle Scholar
  167. Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507(7492):376–380. CrossRefPubMedPubMedCentralGoogle Scholar
  168. Rao SS, O'Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, Van der Ploeg LH, Carroll PM, Draetta GF, Look AT, Strack PR, Winter CG (2009) Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res 69(7):3060–3068. CrossRefPubMedGoogle Scholar
  169. Rasi S, Khiabanian H, Ciardullo C, Terzi-di-Bergamo L, Monti S, Spina V, Bruscaggin A, Cerri M, Deambrogi C, Martuscelli L, Biasi A, Spaccarotella E, De Paoli L, Gattei V, Foa R, Rabadan R, Gaidano G, Rossi D (2016) Clinical impact of small subclones harboring NOTCH1, SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia. Haematologica 101(4):e135–e138. CrossRefPubMedPubMedCentralGoogle Scholar
  170. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, Sulis ML, Barnes K, Sawai C, Homminga I, Meijerink J, Aifantis I, Basso G, Cordon-Cardo C, Ai W, Ferrando A (2009) Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 15 (1):50-58. doi:nm.1900 [pii]
  171. Reizis B, Leder P (2002) Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev 16(3):295–300CrossRefPubMedPubMedCentralGoogle Scholar
  172. Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, Strobl LJ, Honjo T, Clevers H, Radtke F (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 9 (4):377-383. doi:embor20087 [pii]
  173. Rich BE, Campos-Torres J, Tepper RI, Moreadith RW, Leder P (1993) Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J Exp Med 177(2):305–316CrossRefPubMedGoogle Scholar
  174. Roderick JE, Tesell J, Shultz LD, Brehm MA, Greiner DL, Harris MH, Silverman LB, Sallan SE, Gutierrez A, Look AT, Qi J, Bradner JE, Kelliher MA (2014) c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood 123(7):1040–1050. CrossRefPubMedPubMedCentralGoogle Scholar
  175. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, Marasca R, Laurenti L, Bruscaggin A, Cerri M, Monti S, Cresta S, Fama R, De Paoli L, Bulian P, Gattei V, Guarini A, Deaglio S, Capello D, Rabadan R, Pasqualucci L, Dalla-Favera R, Foa R, Gaidano G (2012a) Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 119(2):521–529. CrossRefPubMedPubMedCentralGoogle Scholar
  176. Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Fama R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbo F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R, Facchetti F, Arcaini L, Inghirami G, Bertoni F, Pileri SA, Deaglio S, Foa R, Dalla-Favera R, Pasqualucci L, Rabadan R, Gaidano G (2012b) The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med 209(9):1537–1551. jem.20120904 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  177. Rossi D, Spina V, Bomben R, Rasi S, Dal-Bo M, Bruscaggin A, Rossi FM, Monti S, Degan M, Ciardullo C, Serra R, Zucchetto A, Nomdedeu J, Bulian P, Grossi A, Zaja F, Pozzato G, Laurenti L, Efremov DG, Di-Raimondo F, Marasca R, Forconi F, Del Poeta G, Gaidano G, Gattei V (2013) Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. Blood 121(24):4902–4905. CrossRefPubMedGoogle Scholar
  178. Roti G, Stegmaier K (2014) New Approaches to Target T-ALL. Front Oncol 4:170. CrossRefPubMedPubMedCentralGoogle Scholar
  179. Roti G, Carlton A, Ross KN, Markstein M, Pajcini K, Su AH, Perrimon N, Pear WS, Kung AL, Blacklow SC, Aster JC, Stegmaier K (2013) Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 23(3):390–405. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  180. Ryan RJ, Drier Y, Whitton H, Cotton MJ, Kaur J, Issner R, Gillespie S, Epstein CB, Nardi V, Sohani AR, Hochberg EP, Bernstein BE (2015) Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma. Cancer Discov 5(10):1058–1071. CrossRefPubMedPubMedCentralGoogle Scholar
  181. Ryan R, Petrovic J, Rausch D, Lareau C, Lee W, Donohue L, Christie A, Gillespie S, Kluk M, Nardi V, Faryabi R, Hochberg E, Weinstock D, Bernstein B, Aster J, Pear W (2016) Notch-regulated enhancers in B-cell lymphoma activate MYC and potentiate B-cell receptor signaling. Blood – ASH Annual Meeting Abstracts 128(22):457Google Scholar
  182. Sade H, Krishna S, Sarin A (2004) The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 279(4):2937–2944CrossRefPubMedGoogle Scholar
  183. Salat D, Liefke R, Wiedenmann J, Borggrefe T, Oswald F (2008) ETO, but not leukemogenic fusion protein AML1/ETO, augments RBP-Jkappa/SHARP-mediated repression of notch target genes. Mol Cell Biol 28(10):3502–3512. CrossRefPubMedPubMedCentralGoogle Scholar
  184. Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC (2004) Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 24(21):9265–9273CrossRefPubMedPubMedCentralGoogle Scholar
  185. Sanchez-Martin M, Ambesi-Impiombato A, Qin Y, Herranz D, Bansal M, Girardi T, Paietta E, Tallman MS, Rowe JM, De Keersmaecker K, Califano A, Ferrando AA (2017) Synergistic antileukemic therapies in NOTCH1-induced T-ALL. Proc Natl Acad Sci U S A.
  186. Sanda T, Lawton LN, Barrasa MI, Fan ZP, Kohlhammer H, Gutierrez A, Ma W, Tatarek J, Ahn Y, Kelliher MA, Jamieson CH, Staudt LM, Young RA, Look AT (2012) Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia. Cancer Cell 22(2):209–221. S1535-6108(12)00256-5 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  187. Sawai CM, Freund J, Oh P, Ndiaye-Lobry D, Bretz JC, Strikoudis A, Genesca L, Trimarchi T, Kelliher MA, Clark M, Soulier J, Chen-Kiang S, Aifantis I (2012) Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell 22(4):452–465. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Schnell SA, Ambesi-Impiombato A, Sanchez-Martin M, Belver L, Xu L, Qin Y, Kageyama R, Ferrando AA (2015) Therapeutic targeting of HES1 transcriptional programs in T-ALL. Blood 125(18):2806–2814. CrossRefPubMedPubMedCentralGoogle Scholar
  189. Scripture-Adams DD, Damle SS, Li L, Elihu KJ, Qin S, Arias AM, Butler RR, 3rd, Champhekar A, Zhang JA, Rothenberg EV (2014) GATA-3 dose-dependent checkpoints in early T cell commitment. J Immunol 193 (7):3470-3491.
  190. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, Krishnamoorthy V, Bhasin M, Capobianco AJ, Kelliher MA (2006) Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 26(21):8022–8031CrossRefPubMedPubMedCentralGoogle Scholar
  191. Shimizu D, Taki T, Utsunomiya A, Nakagawa H, Nomura K, Matsumoto Y, Nishida K, Horiike S, Taniwaki M (2007) Detection of NOTCH1 mutations in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. Int J Hematol 85(3):212–218. CrossRefPubMedGoogle Scholar
  192. Shin HM, Minter LM, Cho OH, Gottipati S, Fauq AH, Golde TE, Sonenshein GE, Osborne BA (2006) Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J 25(1):129–138. CrossRefPubMedGoogle Scholar
  193. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, Cario G, Cazzaniga G, Kulozik AE, Stanulla M, Schrappe M, Biondi A, Basso G, Bercovich D, Muckenthaler MU, Izraeli S (2011) Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med 208(5):901–908. doi:jem.20110580 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  194. Shukla V, Shukla A, Joshi SS, Lu R (2016) Interferon regulatory factor 4 attenuates notch signaling to suppress the development of chronic lymphocytic leukemia. Oncotarget.
  195. Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q, Ferrando AA, Levin SD, Geng Y, von Boehmer H, Sicinski P (2003) Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4(6):451–461CrossRefPubMedGoogle Scholar
  196. Song C, Gowda C, Pan X, Ding Y, Tong Y, Tan BH, Wang H, Muthusami S, Ge Z, Sachdev M, Amin SG, Desai D, Gowda K, Gowda R, Robertson GP, Schjerven H, Muschen M, Payne KJ, Dovat S (2015a) Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood 126(15):1813–1822. CrossRefPubMedPubMedCentralGoogle Scholar
  197. Song C, Pan X, Ge Z, Gowda C, Ding Y, Li H, Li Z, Yochum G, Muschen M, Li Q, Payne KJ, Dovat S (2015b) Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia. Leukemia.
  198. Sportoletti P, Baldoni S, Cavalli L, Del Papa B, Bonifacio E, Ciurnelli R, Bell AS, Di Tommaso A, Rosati E, Crescenzi B, Mecucci C, Screpanti I, Marconi P, Martelli MF, Di Ianni M, Falzetti F (2010) NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol 151(4):404–406. CrossRefPubMedGoogle Scholar
  199. Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT (2002) Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99(7):2369–2378CrossRefPubMedGoogle Scholar
  200. Stoeck A, Lejnine S, Truong A, Pan L, Wang H, Zang C, Yuan J, Ware C, MacLean J, Garrett-Engele PW, Kluk M, Laskey J, Haines BB, Moskaluk C, Zawel L, Fawell S, Gilliland G, Zhang T, Kremer BE, Knoechel B, Bernstein BE, Pear WS, Liu XS, Aster JC, Sathyanarayanan S (2014) Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. Cancer Discov 4(10):1154–1167. CrossRefPubMedPubMedCentralGoogle Scholar
  201. Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI (2001) Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413(6853):316–322. CrossRefPubMedGoogle Scholar
  202. Sulis ML, Williams O, Palomero T, Tosello V, Pallikuppam S, Real PJ, Barnes K, Zuurbier L, Meijerink JP, Ferrando AA (2008) NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 112(3):733–740. CrossRefPubMedPubMedCentralGoogle Scholar
  203. Tan Y, Sementino E, Xu J, Pei J, Liu Z, Ito TK, Cai KQ, Peri S, Klein-Szanto AJ, Wiest DL, Testa JR (2017) The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling. Oncotarget.
  204. Tatarek J, Cullion K, Ashworth T, Gerstein R, Aster JC, Kelliher MA (2011) Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood 118(6):1579–1590. blood-2010-08-300343 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  205. Thiel VN, Giaimo BD, Schwarz P, Soller K, Vas V, Bartkuhn M, Blatte TJ, Dohner K, Bullinger L, Borggrefe T, Geiger H, Oswald F (2017) Heterodimerization of AML1/ETO with CBFbeta is required for leukemogenesis but not for myeloproliferation. Leukemia.
  206. Thomas M, Calamito M, Srivastava B, Maillard I, Pear WS, Allman D (2007) Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation. Blood 109(8):3342–3350CrossRefPubMedGoogle Scholar
  207. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, Ferrando A, Aifantis I (2007) The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 204(8):1825–1835CrossRefPubMedPubMedCentralGoogle Scholar
  208. Tosello V, Ferrando AA (2013) The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol 4(3):199–210. 10.1177_2040620712471368 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  209. Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, Aifantis I (2014) Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158(3):593–606. CrossRefPubMedPubMedCentralGoogle Scholar
  210. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E, De Gunzburg N, Payet-Bornet D, Lhermitte L, Mossafa H, Lheritier V, Bond J, Huguet F, Buzyn A, Leguay T, Cahn JY, Thomas X, Chalandon Y, Delannoy A, Bonmati C, Maury S, Nadel B, Macintyre E, Ifrah N, Dombret H, Asnafi V (2013) Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 31(34):4333–4342. CrossRefPubMedGoogle Scholar
  211. Troen G, Wlodarska I, Warsame A, Hernandez Llodra S, De Wolf-Peeters C, Delabie J (2008) NOTCH2 mutations in marginal zone lymphoma. Haematologica 93(7):1107–1109. CrossRefPubMedGoogle Scholar
  212. Uren AG, Kool J, Matentzoglu K, de Ridder J, Mattison J, van Uitert M, Lagcher W, Sie D, Tanger E, Cox T, Reinders M, Hubbard TJ, Rogers J, Jonkers J, Wessels L, Adams DJ, van Lohuizen M, Berns A (2008) Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks. Cell 133 (4):727-741. doi:S0092-8674(08)00436-4 [pii]
  213. Valls E, Lobry C, Geng H, Wang L, Cardenas M, Rivas M, Cerchietti L, Oh P, Yang SN, Oswald E, Graham CW, Jiang Y, Hatzi K, Agirre X, Perkey E, Li Z, Tam W, Bhatt K, Leonard JP, Zweidler-McKay PA, Maillard I, Elemento O, Ci W, Aifantis I, Melnick A (2017) BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells. Cancer Discov.
  214. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M, Tosello V, Della Gatta G, Paietta E, Racevskis J, Wiernik PH, Luger SM, Rowe JM, Rue M, Ferrando AA (2011) ETV6 mutations in early immature human T cell leukemias. J Exp Med 208(13):2571–2579. CrossRefPubMedPubMedCentralGoogle Scholar
  215. VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, Tran IT, Maillard I, Siebel C, Kolterud A, Grosse AS, Gumucio DL, Ernst SA, Tsai YH, Dempsey PJ, Samuelson LC (2012) Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139(3):488–497. dev.070763 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  216. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, Kee BL, Ferrando A, Miele L, Aifantis I (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13(1):70–77. doi:nm1524 [pii]. CrossRefPubMedGoogle Scholar
  217. Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, Georgopoulos K (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5(6):537–549CrossRefPubMedGoogle Scholar
  218. Wang H, Zou J, Zhao B, Johannsen E, Ashworth T, Wong H, Pear WS, Schug J, Blacklow SC, Arnett KL, Bernstein BE, Kieff E, Aster JC (2011a) Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proc Natl Acad Sci U S A 108(36):14908–14913. 1109023108 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  219. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (2011b) SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 365(26):2497–2506. CrossRefPubMedPubMedCentralGoogle Scholar
  220. Wang H, Zang C, Taing L, Arnett KL, Wong YJ, Pear WS, Blacklow SC, Liu XS, Aster JC (2014) NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc Natl Acad Sci U S A 111(2):705–710. [pii]CrossRefPubMedGoogle Scholar
  221. Wang Z, Hu Y, Xiao D, Wang J, Liu C, Xu Y, Shi X, Jiang P, Huang L, Li P, Liu H, Qing G (2017) Stabilization of Notch1 by the Hsp90 Chaperon is Crucial for T Cell Leukemogenesis. Clin Cancer Res.
  222. Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG, Jr. (2005) The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 8 (1):25-33.
  223. Wei G, Abraham BJ, Yagi R, Jothi R, Cui K, Sharma S, Narlikar L, Northrup DL, Tang Q, Paul WE, Zhu J, Zhao K (2011) Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35(2):299–311. CrossRefPubMedPubMedCentralGoogle Scholar
  224. Welcker M, Orian A, Jin J, Grim JA, Harper JW, Eisenman RN, Clurman BE (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A 101(24):9085–9090CrossRefPubMedPubMedCentralGoogle Scholar
  225. Wendorff AA, Koch U, Wunderlich FT, Wirth S, Dubey C, Bruning JC, MacDonald HR, Radtke F (2010) Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33(5):671–684. doi:S1074-7613(10)00420-6 [pii]. CrossRefPubMedGoogle Scholar
  226. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, Aster JC (2003) Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 23(2):655–664CrossRefPubMedPubMedCentralGoogle Scholar
  227. Weng AP, Ferrando AA, Lee W, JPt M, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271CrossRefPubMedGoogle Scholar
  228. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20(15):2096–2109CrossRefPubMedPubMedCentralGoogle Scholar
  229. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O'Rourke KM, Pujara K, Kohli PB, Johnson AR, Chiu ML, Lill JR, Jackson PK, Fairbrother WJ, Seshagiri S, Ludlam MJ, Leong KG, Dueber EC, Maecker H, Huang DC, Dixit VM (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471(7336):110–114. nature09779 [pii]CrossRefPubMedGoogle Scholar
  230. Witkowski MT, Cimmino L, Hu Y, Trimarchi T, Tagoh H, McKenzie MD, Best SA, Tuohey L, Willson TA, Nutt SL, Busslinger M, Aifantis I, Smyth GK, Dickins RA (2015) Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. Leukemia 29(6):1301–1311. CrossRefPubMedPubMedCentralGoogle Scholar
  231. Wouters BJ, Alberich Jorda M, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D, Langerak AW, He Y, Yashiro-Ohtani Y, Zhang P, Hetherington CJ, Verhaak RG, Valk PJ, Lowenberg B, Tenen DG, Pear WS, Delwel R (2007) Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 110(10):3706–3714.
  232. Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464 (7291):1052-1057. nature08878 [pii]
  233. Xu W, Carr T, Ramirez K, McGregor S, Sigvardsson M, Kee BL (2013) E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121(9):1534–1542. CrossRefPubMedPubMedCentralGoogle Scholar
  234. Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI (2004) Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 23(10):2116–2125CrossRefPubMedPubMedCentralGoogle Scholar
  235. Yao D, Huang Y, Huang X, Wang W, Yan Q, Wei L, Xin W, Gerson S, Stanley P, Lowe JB, Zhou L (2011) Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood 117(21):5652–5662. CrossRefPubMedPubMedCentralGoogle Scholar
  236. Yashiro-Ohtani Y, He Y, Ohtani T, Jones ME, Shestova O, Xu L, Fang TC, Chiang MY, Intlekofer AM, Blacklow SC, Zhuang Y, Pear WS (2009) Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev 23(14):1665–1676. doi:23/14/1665 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  237. Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W, Ho Y, Knoechel B, Lanauze C, Louis L, Forsyth KS, Chen S, Chung Y, Schug J, Blobel GA, Liebhaber SA, Bernstein BE, Blacklow SC, Liu XS, Aster JC, Pear WS (2014) Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc Natl Acad Sci U S A 111(46):E4946–E4953. CrossRefPubMedPubMedCentralGoogle Scholar
  238. Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O, Judde JG, Lelievre JD, Levy Y, Benkirane M (2012) NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell 48(3):445–458. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  239. Yoda M, Kimura T, Tohmonda T, Uchikawa S, Koba T, Takito J, Morioka H, Matsumoto M, Link DC, Chiba K, Okada Y, Toyama Y, Horiuchi K (2011) Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis. Blood 118(26):6939–6942. CrossRefPubMedGoogle Scholar
  240. Yu S, Zhao DM, Jothi R, Xue HH (2010) Critical requirement of GABPalpha for normal T cell development. J Biol Chem 285(14):10179–10188. CrossRefPubMedPubMedCentralGoogle Scholar
  241. Yu VW, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Ferraro F, Raaijmakers MH, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT (2015) Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 212(5):759–774. CrossRefPubMedPubMedCentralGoogle Scholar
  242. Yuan T, Yang Y, Chen J, Li W, Li W, Zhang Q, Mi Y, Goswami RS, You JQ, Lin D, Qian MD, Calin S, Liang Y, Miranda RN, Calin GA, Zhou X, Ma L, Zweidler-Mc PA, Liu B, Weng AP, Medeiros LJ, Zhang Y, You MJ (2017) Regulation of PI3K signaling in T cell acute lymphoblastic leukemia: A novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia.
  243. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA, Barata JT (2011) Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. [pii]
  244. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG (2012) The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481(7380):157–163. [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  245. Zhao B, Zou J, Wang H, Johannsen E, Peng CW, Quackenbush J, Mar JC, Morton CC, Freedman ML, Blacklow SC, Aster JC, Bernstein BE, Kieff E (2011) Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci U S A 108(36):14902–14907. 1108892108 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  246. Zhou L, Li LW, Yan Q, Petryniak B, Man Y, Su C, Shim J, Chervin S, Lowe JB (2008) Notch-dependent control of myelopoiesis is regulated by fucosylation. Blood 112(2):308–319. CrossRefPubMedPubMedCentralGoogle Scholar
  247. Zuurbier L, Petricoin EF, 3rd, Vuerhard MJ, Calvert V, Kooi C, Buijs-Gladdines JG, Smits WK, Sonneveld E, Veerman AJ, Kamps WA, Horstmann M, Pieters R, Meijerink JP (2012) The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica 97 (9):1405-1413.
  248. Zweidler-McKay PA, Deangelo DJ, Douer D, Dombret H, Ottoman OG, Vey N, Thomas DA, Zhu L, Huang F, Bajaj G, Fischer BS (2014) The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial Blood (ASH Annual Meeting Abstracts) 124 (21)Google Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cell and Molecular Biology ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Division of Hematology-Oncology, Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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