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NF1 Mutations in Hematologic Cancers

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Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant cancer predisposition syndrome that is caused by germ line mutations in the NF1 tumor suppressor gene. Children with NF1 are at greatly increased risk of developing myeloid malignancies, particularly an aggressive myeloproliferative neoplasm called juvenile myelomonocytic leukemia (JMML). The association between NF1 and JMML prompted the discovery of NF1 as a bona fide tumor suppressor gene in hematopoietic cells whose loss plays a key role in tumorigenesis through increased Ras output. This link also led to the discovery of JMML as fundamentally a disease of hyperactive Ras. Although anecdotal data suggest that patients with NF1 are at increased risk of developing leukemia after receiving genotoxins to treat another primary cancer, adults with NF1 are not predisposed to spontaneously develop hematologic cancers for unknown reasons. With the advent of new technologies for genome-wide analysis, NF1 is emerging as an important tumor suppressor in sporadic cancers, including acute myeloid leukemia. Studies in animal models have shown that Nf1 inactivation initiates myeloid leukemia in vivo and are suggesting new therapeutic strategies for treating JMML and other hematologic cancers. In this chapter, we address the role of NF1 mutations in hematologic cancers and emphasize recent advances in the field, therapeutic options, unanswered questions, and future directions.

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References

  • Bader JL, Miller RW (1978) Neurofibromatosis and childhood leukemia. J Pediatr 92:925–929

    Article  PubMed  CAS  Google Scholar 

  • Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo HB, Terlouw-Kromosoeto JN, van Wering ER, Reinhardt D, Horstmann M, Kaspers GJ, Pieters R, Zwaan CM, Van den Heuvel-Eibrink MM, Meijerink JP (2008) Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 111:4322–4328

    Article  PubMed  CAS  Google Scholar 

  • Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J (1992) Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356:713–715

    Article  PubMed  CAS  Google Scholar 

  • Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM (2000) Nf1 and Gmcsf interact in myeloid leukemogenesis. Mol Cell 5:189–195

    Article  PubMed  CAS  Google Scholar 

  • Bollag G, Clapp DW, Shih S, Adler F, Zhang Y, Thompson P, Lange BJ, Freedman MH, McCormick F, Jacks T, Shannon K (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in murine and human hematopoietic cells. Nat Genet 12:144–148

    Article  PubMed  CAS  Google Scholar 

  • Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins N, Parada L, Copeland N (1994) Targeted disruption of the neurofibromatosis type 1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 8:1019–1029

    Article  PubMed  CAS  Google Scholar 

  • Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J, Le Beau MM, Jacks TE, Shannon KM (2004) Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA 101:597–602

    Article  PubMed  CAS  Google Scholar 

  • Cancer Genome Atlas Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  • Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H, Johnson L, Akashi K, Tuveson DA, Jacks T, Gilliland DG (2004) Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest 113:528–538

    PubMed  CAS  Google Scholar 

  • Chang T, Krisman K, Braun BS, Shannon K (2011) MEK inhibition modulates the growth of Nf1 mutant hematopoietic cells and induces clinical improvement in a murine model of JMML (abstract). Blood 118:797

    Article  Google Scholar 

  • Chao RC, Pyzel U, Fridlyand J, Kuo YM, Teel L, Haaga J, Borowsky A, Horvai A, Kogan SC, Bonifas J, Huey B, Jacks TE, Albertson DG, Shannon KM (2005) Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell 8:337–348

    Article  PubMed  CAS  Google Scholar 

  • Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, Konig R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E, Pennacchio LA, Gelb BD, Dallapiccola B, Wittinghofer A, Ahmadian MR, Tartaglia M, Zenker M (2010) A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 42:27–29

    Article  PubMed  CAS  Google Scholar 

  • DeClue JE, Cohen BD, Lowy DR (1991) Identification and characterization of the neurofibromatosis type 1 protein product. Proc Natl Acad Sci USA 88:9914–9918

    Article  PubMed  CAS  Google Scholar 

  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba B II, Ozenberger PJ, Good AC, Chang DG, Beer MA, Watson M, Ladanyi S, Broderick A, Yoshizawa WD, Travis W, Pao MA, Province GM, Weinstock HE, Varmus SB, Gabriel ES, Lander RA, Gibbs MM, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  PubMed  CAS  Google Scholar 

  • Dunbar AJ, Gondek LP, O'Keefe CL, Makishima H, Rataul MS, Szpurka H, Sekeres MA, Wang XF, McDevitt MA, Maciejewski JP (2008) 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res 68:10349–10357

    Article  PubMed  CAS  Google Scholar 

  • Emanuel PD, Bates LJ, Castleberry RP, Gualtieri RJ, Zuckerman KS (1991) Selective hypersensitivity to granulocyte-macrophage colony stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77:925–929

    PubMed  CAS  Google Scholar 

  • Flotho C, Steinemann D, Mullighan CG, Neale G, Mayer K, Kratz CP, Schlegelberger B, Downing JR, Niemeyer CM (2007) Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 26:5816–5821

    Article  PubMed  CAS  Google Scholar 

  • Gibbs JB, Oliff A, Kohl NE (1994) Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77:175–178

    Article  PubMed  CAS  Google Scholar 

  • Haferlach C, Dicker F, Kohlmann A, Schindela S, Weiss T, Kern W, Schnittger S, Haferlach T (2010) AML with CBFB-MYH11 rearrangement demonstrate RAS pathway alterations in 92 % of all cases including a high frequency of NF1 deletions. Leukemia 24:1065–1069

    Article  PubMed  CAS  Google Scholar 

  • Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, Nijkamp W, Xie J, Callens T, Asgharzadeh S, Seeger RC, Messiaen L, Versteeg R, Bernards R (2010) NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142:218–229

    Article  PubMed  Google Scholar 

  • Jacks T, Shih S, Schmitt EM, Bronson RT, Bernards A, Weinberg RA (1994) Tumorigenic and developmental consequences of a targeted Nf1 mutation in the mouse. Nat Genet 7:353–361

    Article  PubMed  CAS  Google Scholar 

  • James G, Goldstein JL, Brown MS (1996) Resistance of K-RasBv12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc Natl Acad Sci USA 93:4454–4458

    Article  PubMed  CAS  Google Scholar 

  • Kalra R, Paderanga D, Olson K, Shannon KM (1994) Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras. Blood 84:3435–3439

    PubMed  CAS  Google Scholar 

  • Kaneko Y, Maseki N, Sakuri M, Shibuya A, Shinohara T, Fujimoto T, Kanno H, Nishikawa A (1989) Chromosome patterns in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Leukemia 3:36–41

    PubMed  CAS  Google Scholar 

  • Keilhack H, David FS, McGregor M, Cantley LC, Neel BG (2005) Diverse biochemical properties of Shp2 mutants: implications for disease phenotypes. J Biol Chem 280:30984–30993

    Article  PubMed  CAS  Google Scholar 

  • Kim A, Morgan K, Hasz DE, Wiesner SM, Lauchle JO, Geurts JL, Diers MD, Le DT, Kogan SC, Parada LF, Shannon K, Largaespada DA (2007) Beta common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice. Blood 109:1687–1691

    Article  PubMed  CAS  Google Scholar 

  • Kolquist KA, Schultz RA, Furrow A, Brown TC, Han JY, Campbell LJ, Wall M, Slovak ML, Shaffer LG, Ballif BC (2011) Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes. Cancer Genet 204:603–628

    Article  PubMed  CAS  Google Scholar 

  • Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML (2008) Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell 14:335–343

    Article  PubMed  CAS  Google Scholar 

  • Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M, Loh ML (2005) The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106:2183–2185

    Article  PubMed  CAS  Google Scholar 

  • Kuhn R, Schwenk F, Aguet M, Rajewsky K (1995) Inducible gene targeting in mice. Science 269:1427–1429

    Article  PubMed  CAS  Google Scholar 

  • Largaespada DA, Brannan CI, Jenkins NA, Copeland NG (1996) Nf1 deficiency causes Ras-mediated granulocyte-macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia. Nat Genet 12:137–143

    Article  PubMed  CAS  Google Scholar 

  • Lauchle JO, Braun BS, Loh ML, Shannon K (2006) Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr Blood Cancer 46:579–585

    Article  PubMed  Google Scholar 

  • Lauchle JO, Kim D, Le DT, Akagi K, Crone M, Krisman K, Warner K, Bonifas JM, Li Q, Coakley KM, Diaz-Flores E, Gorman M, Przybranowski S, Tran M, Kogan SC, Roose JP, Copeland NG, Jenkins NA, Parada L, Wolff L, Sebolt-Leopold J, Shannon K (2009) Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461:411–414

    Article  PubMed  CAS  Google Scholar 

  • Laycock-van Spyk S, Thomas N, Cooper DN, Upadhyaya M (2011) Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics 5:623–690

    Article  PubMed  Google Scholar 

  • Le Beau MM, Espinosa R 3rd, Davis EM, Eisenbart JD, Larson RA, Green ED (1996) Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 88:1930–1935

    PubMed  Google Scholar 

  • Le DT, Kong N, Zhu Y, Lauchle JO, Aiyigari A, Braun BS, Wang E, Kogan SC, Le Beau MM, Parada L, Shannon KM (2004) Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 103:4243–4250

    Article  PubMed  CAS  Google Scholar 

  • Loh ML (2011) Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152:677–687

    Article  PubMed  CAS  Google Scholar 

  • Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114:1859–1863

    Article  PubMed  CAS  Google Scholar 

  • Lyubynska N, Gorman MF, Lauchle JO, Hong WX, Akutagawa JK, Shannon K, Braun BS (2011) A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice. Sci Transl Med 3:76ra27

    Google Scholar 

  • Mahgoub N, Taylor B, Le Beau M, Gratiot M, Carlson K, Jacks T, Shannon KM (1999a) Myeloid malignancies induced by alkylating agents in Nf1 mice. Blood 93:3617–3623

    PubMed  CAS  Google Scholar 

  • Mahgoub N, Taylor BR, Gratiot M, Kohl NE, Gibbs JB, Jacks T, Shannon KM (1999b) In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. Blood 94:2469–2476

    PubMed  CAS  Google Scholar 

  • Marchuk DA, Saulino AM, Tavakkol R, Swaroop M, Wallace MR, Andersen LB, Mitchell AL, Gutmann DH, Boguski M, Collins FS (1991) cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11:931–940

    Article  PubMed  CAS  Google Scholar 

  • Maris JM, Wiersma SR, Mahgoub N, Thompson P, Geyer RJ, Lange BJ, Shannon KM (1997) Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 79:1438–1446

    Article  PubMed  CAS  Google Scholar 

  • Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, Skelton NJ, Fauber BP, Pan B, Malek S, Stokoe D, Ludlam MJ, Bowman KK, Wu J, Giannetti AM, Starovasnik MA, Mellman I, Jackson PK, Rudolph J, Wang W, Fang G (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 109:5299–5304

    Article  PubMed  CAS  Google Scholar 

  • Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP et al (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci USA 87:5435–5439

    Article  PubMed  CAS  Google Scholar 

  • Miles DK, Freedman MH, Stephens K, Pallavicini M, Sievers E, Weaver M, Grunberger T, Thompson P, Shannon KM (1996) Patterns of hematopoietic lineage involvement in children with neurofibromatosis, type 1, and malignant myeloid disorders. Blood 88:4314–4320

    PubMed  CAS  Google Scholar 

  • Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S (1994) Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83:2248–2254

    PubMed  CAS  Google Scholar 

  • Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–764

    Article  PubMed  CAS  Google Scholar 

  • Nakamura JL, Phong C, Pinarbasi E, Kogan SC, Vandenberg S, Horvai AE, Faddegon BA, Fiedler D, Shokat K, Houseman BT, Chao R, Pieper RO, Shannon K (2011) Dose-dependent effects of focal fractionated irradiation on secondary malignant neoplasms in Nf1 mutant mice. Cancer Res 71:106–115

    Article  PubMed  CAS  Google Scholar 

  • Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794–800

    Article  PubMed  CAS  Google Scholar 

  • Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, Glassman AB, Albitar M, Kwari MI, Beran M (2002) Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 99:840–849

    Article  PubMed  CAS  Google Scholar 

  • Papageorgio C, Seiter K, Feldman EJ (1999) Therapy-related myelodysplastic syndrome in adults with neurofibromatosis. Leuk Lymphoma 32:605–608

    PubMed  CAS  Google Scholar 

  • Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, Purkayastha A, Dressel A, Karp J, Bockenstedt P, Al-Zoubi A, Talpaz M, Kujawski L, Shedden K, Shakhan S, Li C, Erba H, Malek SN (2010) NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res 16:4135–4147

    Article  PubMed  CAS  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  • Royer P, Blondet C, Guihard J (1958) Xantholeucemie du nourrisson et neurofibromatose de Recklinghausen. Ann Pediatr 24:1504–1513

    Google Scholar 

  • Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S (2009) Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460:904–908

    Article  PubMed  CAS  Google Scholar 

  • Sangha N, Wu R, Kuick R, Powers S, Mu D, Fiander D, Yuen K, Katabuchi H, Tashiro H, Fearon ER, Cho KR (2008) Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia 10:1362–1372

    PubMed  CAS  Google Scholar 

  • Sawyers CL (1999) Chronic myeloid leukemia. N Engl J Med 340:1330–1340

    Article  PubMed  CAS  Google Scholar 

  • Sawyers CL, Denny CT (1994) Chronic myelomonocytic leukemia: tel-a-kinase what ets all about. Cell 77:171–173

    Article  PubMed  CAS  Google Scholar 

  • Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP (2006) Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:331–336

    Article  PubMed  CAS  Google Scholar 

  • Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308

    Article  PubMed  CAS  Google Scholar 

  • Shannon KM, Watterson J, Johnson P, O'Connell P, Lange B, Shah N, Kan YW, Priest JR (1992) Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. Blood 79:1311–1318

    PubMed  CAS  Google Scholar 

  • Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F (1994) Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 330:597–601

    Article  PubMed  CAS  Google Scholar 

  • Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, Shannon K (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 336:1713–1720

    Article  PubMed  CAS  Google Scholar 

  • Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP, Shannon KM (1998) Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92:267–272

    PubMed  CAS  Google Scholar 

  • Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, Vardiman JW, Rowley JD, Larson RA (2003) Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102:43–52

    Article  PubMed  CAS  Google Scholar 

  • Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, Flotho C (2010) Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica 95:320–323

    Article  PubMed  CAS  Google Scholar 

  • Stephens K, Weaver M, Leppig KA, Maruyama K, Emanuel PD, Le Beau MM, Shannon KM (2006) Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood 108:1684–1689

    Article  PubMed  CAS  Google Scholar 

  • Stiller CA, Chessells JM, Fitchett M (1994) Neurofibromatosis and childhood leukemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70:969–972

    Article  PubMed  CAS  Google Scholar 

  • Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468

    Article  PubMed  CAS  Google Scholar 

  • Van Etten RA, Shannon KM (2004) Focus on myeloproliferative diseases and myelodysplastic syndromes. Cancer Cell 6:547–552

    Article  PubMed  Google Scholar 

  • Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O'Connell P (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192

    Article  PubMed  CAS  Google Scholar 

  • Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, Brownstein BH, Collins FS (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186

    Article  PubMed  CAS  Google Scholar 

  • Xu G, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F (1990a) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63:835–841

    Article  PubMed  CAS  Google Scholar 

  • Xu G, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R (1990b) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Vik TA, Ryder JW, Srour EF, Jacks T, Shannon K, Clapp DW (1998) Nf1 regulates hematopoietic progenitor cell growth and Ras signaling in response to multiple cytokines. J Exp Med 187:1893–1902

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Taylor BR, Shannon K, Clapp DW (2001) Quantitative effects of Nf1 inactivation on in vivo hematopoiesis. J Clin Invest 108:709–715

    PubMed  CAS  Google Scholar 

  • Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 15:859–876

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:920–922

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work from our laboratory presented in this chapter was funded, in part, by the US Army Neurofibromatosis Research Program (Project DAMD17-02-1-0638), by NIH grants CA72614 and U0184221, and by the Children’s Tumor Foundation. T.C. is the recipient of a fellowship from the St. Baldrick’s Foundation, and K.S. is an American Cancer Society research professor.

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  1. Department of Pediatrics, University of California, San Francisco, CA, 94158, USA

    Tiffany Chang & Kevin Shannon

  2. Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, USA

    Kevin Shannon

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  1. Tiffany Chang
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Correspondence to Kevin Shannon .

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  1. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park Campus, Cardiff, 144XN, United Kingdom

    Meena Upadhyaya

  2. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom

    David N. Cooper

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Chang, T., Shannon, K. (2012). NF1 Mutations in Hematologic Cancers. In: Upadhyaya, M., Cooper, D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32864-0_30

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