Deregulated NOTCH Signaling in Acute T-Cell Lymphoblastic Leukemia/Lymphoma: New Insights, Questions, and Opportunities

Article

Abstract

Recent work has shown that the majority of human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) have gain-of-function mutations in NOTCH1, a type I transmembrane receptor that normally signals through a 7-secretase-dependent mechanism that relies on ligand-induced regulated intramembranous proteolysis. Cleavage by 7-secretase releases the intracellular domain of NOTCH1 (ICN1), permitting it to translocate to the nucleus and form a short-lived transcriptional activation complex that is essential for normal T-cell development. Two types of mutations are prevalent in human T-ALL: extracellular domain mutations that increase ICN1 production and C-terminal mutations that sustain ICN1 action. Inhibitors of ICN1 production and activity abrogate the growth of established T-ALL cell lines, and a clinical trial of a NOTCH pathway inhibitor in patients with refractory T-ALL has opened recently. These insights raise a number of new questions relevant to T-ALL pathogenesis and offer exciting opportunities for rational targeted therapy.

Key words

NOTCH1 Acute T-cell lymphoblastic leukemia/lymphoma Targeted therapy Leukemic stem cells 

References

  1. 1.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development.Science. 1999;284:770–776.PubMedCrossRefGoogle Scholar
  2. 2.
    Kumano K, Chiba S, Kunisato A, et al. Notchl but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.Immunity. 2003;18:699–711.PubMedCrossRefGoogle Scholar
  3. 3.
    Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything.Curr Opin Genet Dev. 2004;14:48–54.PubMedCrossRefGoogle Scholar
  4. 4.
    Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of theDrosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.Cell. 1991;66:649–661.PubMedCrossRefGoogle Scholar
  5. 5.
    Radtke F, Wilson A, Stark G, et al. Deficient T cell fate specification in mice with an induced inactivation of Notchl.Immunity. 1999;10:547–558.PubMedCrossRefGoogle Scholar
  6. 6.
    Logeat F, Bessia C, Brou C, et al. The Notchl receptor is cleaved constitutively by a furin-like convertase.Proc Natl Acad Sci USA. 1998;95:8108–8112.PubMedCrossRefGoogle Scholar
  7. 7.
    Rand MD, Grimm LM, Artavanis-Tsakonas S, et al. Calcium depletion dissociates and activates heterodimeric Notch receptors.Mol Cell Biol. 2000;20:1825–1835.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats.Mol Cell Biol. 2004;24:9265–9273.PubMedCrossRefGoogle Scholar
  9. 9.
    Schweisguth F. Notch signaling activity.Curr Biol. 2004;14:R129-R138.PubMedGoogle Scholar
  10. 10.
    Fortini ME. γ-Secretase-mediated proteolysis in cell-surfacereceptor signalling.Nat Rev Mol Cell Biol. 2002;3:673–684.PubMedCrossRefGoogle Scholar
  11. 11.
    Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.Mol Cell. 2000;5:207–216.PubMedCrossRefGoogle Scholar
  12. 12.
    Mumm JS, Schroeter EH, Saxena MT, et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic tease TA CE.Mol Cell. 2000;5:207–216.CrossRefGoogle Scholar
  13. 13.
    Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.Nature. 1998;393:382–386.PubMedCrossRefGoogle Scholar
  14. 14.
    De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active γ-Secretase complex.Neuron. 2003;38:9–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Gupta-Rossi N, Six E, LeBail O, et al. Monoubiquitination and endocytosis direct γ-secretase cleavage of activated Notch receptor.J Cell Biol. 2004;166:73–83.PubMedCrossRefGoogle Scholar
  16. 16.
    Struhl G, Adachi A. Nuclear access and action of Notch in vivo.Cell. 1998;93:649–660.PubMedCrossRefGoogle Scholar
  17. 17.
    Struhl G, Grenwald I. Presenilin is required for activity and nuclear access of Notch inDrosophila.Nature. 1999;398:522–525.PubMedCrossRefGoogle Scholar
  18. 18.
    Petcherski AG, Kimble J. LAG-3 is a putative transcriptional activator in theC. elegans Notch pathway.Nature. 2000;405:364–368.PubMedCrossRefGoogle Scholar
  19. 19.
    Wallberg AE, Pedersen K, Lendahl U, Roeder RG. p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by Notch intracellular domains in vitro.Mol Cell Biol. 2002;22:7812–7819.PubMedCrossRefGoogle Scholar
  20. 20.
    Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue ofDrosophila Mastermind, is a transcriptional co-activator for NOTCH receptors.Nat Genet. 2000;26:484–489.PubMedCrossRefGoogle Scholar
  21. 21.
    Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones CA. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.Genes Dev. 2002;16:1397–1411.PubMedCrossRefGoogle Scholar
  22. 22.
    Fryer CJ, White JB, Jones KA. Mastermind recruits CycC: CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.Mol Cell. 2004;16:509–520.PubMedCrossRefGoogle Scholar
  23. 23.
    Jeffries S, Robbins DJ, Capobianco AJ. Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-trans-formed RKE cells and in a human T-cell leukemia cell line.Mol Cell Biol. 2002;22:3927–3941.PubMedCrossRefGoogle Scholar
  24. 24.
    Gupta-Rossi N, Le Bail O, Gonen H, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notchl receptor.J Biol Chem. 2001;276:34371–34378.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu G, Lyapina S, Das I, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation.Mol Cell Biol. 2001;21:7403–7415.PubMedCrossRefGoogle Scholar
  26. 26.
    Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.J Biol Chem. 2001;276:35847–35853.PubMedCrossRefGoogle Scholar
  27. 27.
    Martinez Arias A, Zecchini V, Brennan K. CSL-independent Notch signalling: a checkpoint in cell fate decisions during development?Curr Opin Genet Dev. 2002;12:524–533.CrossRefGoogle Scholar
  28. 28.
    Bush G, diSibio G, Miyamoto A, Denault JB, Leduc R, Weinmaster G. Ligand-induced signaling in the absence of furin processing of Notchl.Dev Biol. 2001;229:494–502.PubMedCrossRefGoogle Scholar
  29. 29.
    Wilson A, MacDonald HR, Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.J Exp Med. 2001;229:494–502.Google Scholar
  30. 30.
    Doerfler P, Shearman MS, Perlmutter RM. Presenilin-dependent γ-secretase activity modulates thymocyte development.Proc Natl Acad Sci USA. 2001;98:9312–9317.PubMedCrossRefGoogle Scholar
  31. 31.
    Koch U, Lacombe TA, Holland D, et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.Immunity. 2001;15:225–236.PubMedCrossRefGoogle Scholar
  32. 32.
    Izon DJ, Aster JC, He Y, et al. Deltexl redirects lymphoid progenitors to the B cell lineage by antagonizing Notchl.Immunity. 2001;15:225–236.CrossRefGoogle Scholar
  33. 33.
    Sambandam A, Maillard I, Zediak VP, et al. Notch signaling controls the generation and differentiation of early T lineage progenitors.Nat Immunol. 2005;6:663–670.PubMedCrossRefGoogle Scholar
  34. 34.
    Tan JB, Visan I, Yuan JS, Guidos CJ. Requirement for Notchl signals at sequential early stages of intrathymic T cell development.Nat Immunol. 2005;6:671–679.PubMedCrossRefGoogle Scholar
  35. 35.
    Radtke F, Wilson A, Mancini SJ, MacDonald HR. Notch regulation of lymphocyte development and function.Nat Immunol. 2004;5:247–253.PubMedCrossRefGoogle Scholar
  36. 36.
    Hadland BK, Manley NR, Su D, et al. γ-Secretase inhibitors repress thymocyte development.Proc Natl Acad Sci USA. 2001;98:7487–7491.PubMedCrossRefGoogle Scholar
  37. 37.
    Tanigaki K, Tsuji M, Yamamoto N, et al. Regulation of αβ/7δ T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.Immunity. 2004;20:611–622.PubMedCrossRefGoogle Scholar
  38. 38.
    Maillard I, Weng AP, Carpenter AC, et al. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions.Blood. 2004;20:611–622.Google Scholar
  39. 39.
    Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.J Exp Med. 1996;183:2283–2291.PubMedCrossRefGoogle Scholar
  40. 40.
    Bellavia D, Campese AF, Alesse E, et al. Constitutive activation of NF-kB and T-cell leukemia/lymphoma in Notch3 transgenic mice.EMBO J. 2000;19:3337–3348.PubMedCrossRefGoogle Scholar
  41. 41.
    Weng AP, Nam Y, Wolfe MS, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of Notch signaling.Mol Cell Biol. 2003;23:655–664.PubMedCrossRefGoogle Scholar
  42. 42.
    Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.Science. 2003;23:655–664.Google Scholar
  43. 43.
    Asnafi V, Beldjord K, Boulanger E, et al. Analysis of TCR, pTα, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment.Blood. 2003;101:2693–2703.PubMedCrossRefGoogle Scholar
  44. 44.
    Ferrando AA, Look AT. Gene expression profiling in T-cell acute lymphoblastic leukemia.Semin Hematol. 2003;40:274–280.PubMedCrossRefGoogle Scholar
  45. 45.
    Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.Cancer atol. 2003;40:274–280.Google Scholar
  46. 46.
    Greenwald I, Seydoux G. Analysis of gain-of-function mutations of thelin-12 gene ofCaenorhabditis elegans.Nature. 1990;346:197–199.PubMedCrossRefGoogle Scholar
  47. 47.
    Mango SE, Maine EM, Kimble J. Carboxy-terminal truncation activates glp-1 protein to specify vulval fates inCaenorhabditis elegans.Nature. 1991;352:811–815.PubMedCrossRefGoogle Scholar
  48. 48.
    Berry LW, Westlund B, Schedl T. Germ-line tumor formation caused by activation of glp-1, aCaenorhabditis elegans member of the Notch family of receptors.Development. 1997;124:925–936.PubMedGoogle Scholar
  49. 49.
    Feldman BJ, Hampton T, Cleary ML. A carboxy-terminal deletion mutant of Notchl accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice.Blood. 2000;96:1906–1913.PubMedGoogle Scholar
  50. 50.
    Hoemann CD, Beaulieu N, Girard L, Rebai N, Jolicoeur P. Two distinctNotchl mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice.Mol Cell Biol. 2000;20:3831–3842.PubMedCrossRefGoogle Scholar
  51. 51.
    Hubbard EJ, Wu G, Kitajewski J, Greenwald I.sel-10, a negative regulator oflin-12 activity inCaenorhabditis elegans, encodes a member of the CDC4 family of proteins.Genes Dev. 1997;11:3182–3193.PubMedCrossRefGoogle Scholar
  52. 52.
    Tetzlaff MT, Yu W, Li M, et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.Proc Natl Acad Sci USA. 2004;101:3338–3345.PubMedCrossRefGoogle Scholar
  53. 53.
    Tsunematsu R, Nakayama K, Oike Y, et al. Mouse Fbw7/Sel-10/Cdc4 is required for Notch degradation during vascular development.J Biol Chem. 2004;279:9417–9423.PubMedCrossRefGoogle Scholar
  54. 54.
    Girand L, Hanna Z, Beaulieu N, et al. Frequent proviral insertional mutagenesis ofNOTCH1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc andNOTCH1 for oncogenesis.Genes Dev. 1996;10:1930–1944.CrossRefGoogle Scholar
  55. 55.
    Beverly LJ, Capobianco AJ. Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)induced T cell leukemogenesis.Cancer Cell. 2003;3:551–564.PubMedCrossRefGoogle Scholar
  56. 56.
    Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notchl signaling.Nat Med. 2000;6:1278–1281.PubMedCrossRefGoogle Scholar
  57. 57.
    Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. Notchl activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.Blood. 2002;99:2369–2378.PubMedCrossRefGoogle Scholar
  58. 58.
    Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche.Nature. 2003;425:841–846.PubMedCrossRefGoogle Scholar
  59. 59.
    Duncan AW, Rattis FM, Dimascio LN, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.Nat Immunol. 2005;6:314–322.PubMedCrossRefGoogle Scholar
  60. 60.
    Pui JC, Allman D, Xu L, et al. Notchl expression in early lymphopoiesis influences B versus T lineage determination.Immunity. 1999;ll:299–308.CrossRefGoogle Scholar
  61. 61.
    Izon DJ, Punt JA, Xu L, et al. Notchl regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength.Immunity. 2001;14:253–264.PubMedCrossRefGoogle Scholar
  62. 62.
    Tsuji H, Ishii-Ohba H, Ukai H, Katsube T, Ogiu T. Radiation-induced deletions in the 5′ end region of Notchl lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas.Carcinogenesis. 2003;24:1257–1268.PubMedCrossRefGoogle Scholar
  63. 63.
    Yan XQ, Sarmiento U, Sun Y, et al. A novel Notch ligand, D114, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer.Blood. 2001;98:3793–3799.PubMedCrossRefGoogle Scholar
  64. 64.
    Rohn JL, Lauring AS, Linenberger ML, Overbaugh J. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma.J Virol. 1996;70:8071–8080.PubMedGoogle Scholar
  65. 65.
    Selkoe D, Kopan R. Notch and Presenilin: regulated intramem-brane proteolysis links development and degeneration.Annu Rev Neurosci. 2003;26:565–597.PubMedCrossRefGoogle Scholar
  66. 66.
    Kopan R, Ilagan MX. γ-Secretase: proteasome of the membrane?Nat Rev Mol Cell Biol. 2004;5:499–504.PubMedCrossRefGoogle Scholar
  67. 67.
    Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A. Mice lacking both presenilin genes exhibit early embryonic patterning defects.Genes Dev. 1999;13:2801–2810.PubMedCrossRefGoogle Scholar
  68. 68.
    Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish.EMBO Rep. 2002;3:688–694.PubMedCrossRefGoogle Scholar
  69. 69.
    Micchelli CA, Esler WP, Kimberly WT, et al. γ-Secretase/presenilin inhibitors for Alzheimer’s disease phenocopyNotch mutations inDrosophila.FASEB J. 2003;17:79–81.PubMedGoogle Scholar
  70. 70.
    Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.J Biol Chem. 2004;279:12876–12882.PubMedCrossRefGoogle Scholar
  71. 71.
    Marjaux E, Hartmann D, De Strooper B. Presenilins in memory, Alzheimer’s disease, and therapy.Neuron. 2004;42:189–192.PubMedCrossRefGoogle Scholar
  72. 72.
    Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.J Cell Biol. 2004;167:215–221.PubMedCrossRefGoogle Scholar
  73. 73.
    Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis.Cancer Cell. 2003;3:565–576.PubMedCrossRefGoogle Scholar
  74. 74.
    Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.Cancer Res. 2005;65:2353–2363.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2005

Authors and Affiliations

  1. 1.Department of PathologyBrigham and Women’s HospitalBostonUSA

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