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Signal Transduction of Oncogenic Flt3

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Abstract

Activating mutations of Fms-like tyrosine kinase 3 (Flt3) are the most common genetic lesions in acute myeloid leukemia (AML) and are present in approximately one third of AML patients. The 2 classes of Flt3 mutations are internal tandem duplications in the juxtamembrane domain and point mutations in the tyrosine kinase domain. In normal hematopoietic progenitor cells, Flt3 ligand induces the activation of several downstream signal-transduction mediators, including phosphoinos-itol 3-kinases, Src kinases, mitogen-activated protein kinases, and the phosphorylation of several adaptor proteins. Oncogenic mutations in Flt3 result in ligand-independent constitutive and deregulated activation of these signaling pathways. In addition, however, oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-α and Pu.1. Aberrant activation of these signaling pathways by oncogenic Flt3 may play a critical role in mutant Flt3-mediated leukemic transformation.

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References

  1. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies.Nat Rev Cancer. 2003;3:650–665.

    Article  CAS  PubMed  Google Scholar 

  2. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia.Blood. 2002;100:1532–1542.

    Article  CAS  PubMed  Google Scholar 

  3. Carow CE, Kim E, Hawkins AL, et al. Localization of the human stem cell tyrosine kinase-1 gene (FLT3) to 13q12—>q13.Cytogenet Cell Genet. 1995;70:255–257.

    Article  PubMed  CAS  Google Scholar 

  4. Maroc N, Rottapel R, Rosnet O, et al. Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase.Oncogene. 1993;8:909–918.

    PubMed  CAS  Google Scholar 

  5. Lyman SD, James L, Zappone J, Sleath PR, Beckmann MP, Bird T. Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene.Oncogene. 1993;8:815–822.

    CAS  PubMed  Google Scholar 

  6. Small D, Levenstein M, Kim E, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/ stem cells.Proc Natl Acad Sci U S A. 1994;91:459–463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations.Cell. 1991;65:1143–1152.

    Article  CAS  PubMed  Google Scholar 

  8. Schmidt-Arras D, Schwable J, Bohmer FD, Serve H. Flt3 receptor tyrosine kinase as a drug target in leukemia.Curr Pharm Des. 2004; 10:1867–1883.

    Article  PubMed  CAS  Google Scholar 

  9. Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT- like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages.Blood. 1992;80:2584–2593.

    CAS  PubMed  Google Scholar 

  10. Rosnet O, Buhring HJ, deLapeyriere O, et al. Expression and signal transduction of the FLT3 tyrosine kinase receptor.Acta Haematol. 1996;95:218–223.

    Article  CAS  PubMed  Google Scholar 

  11. Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias.Blood. 1996;87:1089–1096.

    CAS  PubMed  Google Scholar 

  12. Lyman SD, James L, Johnson L, et al. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells.Blood. 1994;83:2795–2801.

    PubMed  CAS  Google Scholar 

  13. Lyman SD, James L, Vanden Bos T, et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells.Cell. 1993;75:1157–1167.

    Article  PubMed  CAS  Google Scholar 

  14. Hannum C, Culpepper J, Campbell D, et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.Nature. 1994;368:643–648.

    Article  CAS  PubMed  Google Scholar 

  15. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.Leukemia. 1996;10:1911–1918.

    CAS  PubMed  Google Scholar 

  16. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.Blood. 2002;99:4326–4335.

    Article  CAS  PubMed  Google Scholar 

  17. Armstrong SA, Mabon ME, Silverman LB, et al. FLT3 mutations in childhood acute lymphoblastic leukemia.Blood. 2004;103:3544–3546.

    Article  CAS  PubMed  Google Scholar 

  18. Horiike S, Yokota S, Nakao M, et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia.Leukemia. 1997;11:1442–1446.

    Article  CAS  PubMed  Google Scholar 

  19. Yokota S, Kiyoi H, Nakao M, et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies: a study on a large series of patients and cell lines.Leukemia. 1997;11:1605–1609.

    Article  CAS  PubMed  Google Scholar 

  20. Steudel C, Wermke M, Schaich M, et al. Comparative analysis ofMLL partial tandem duplication andFLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia.Genes Chromosomes Cancer. 2003;37:237–251.

    Article  CAS  PubMed  Google Scholar 

  21. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.Blood. 2001;97:2434–2439.

    Article  CAS  PubMed  Google Scholar 

  22. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia.Br J Haematol. 2001;113:983–988.

    Article  CAS  PubMed  Google Scholar 

  23. Spiekermann K, Bagrintseva K, Schoch C, Haferlach T, Hiddemann W, Schnittger S. A new and recurrent activating length mutation in exon 20 of theFLT3 gene in acute myeloid leukemia.Blood. 2002; 100:3423–3425.

    Article  CAS  PubMed  Google Scholar 

  24. Kindler T, Breitenbuecher F, Kasper S, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).Blood. 2005;105:335–340.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang J, Paez JG, Lee JC, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.Blood. 2004;104:1855–1858.

    Article  PubMed  CAS  Google Scholar 

  26. Hayakawa F, Towatari M, Kiyoi H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines.Oncogene. 2000;19:624–631.

    Article  PubMed  CAS  Google Scholar 

  27. Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.Blood. 2000;96:3907–3914.

    PubMed  CAS  Google Scholar 

  28. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model.Blood. 2002;99:310–318.

    Article  PubMed  CAS  Google Scholar 

  29. Kelly LM, Kutok JL, Williams IR, et al. PML/RARα and FLT3- ITD induce an APL-like disease in a mouse model.Proc NatlAcad Sci U S A. 2002;99:8283–8288.

    Article  CAS  Google Scholar 

  30. Sohal J, Phan VT, Chan PV, et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657.Blood. 2003;101:3188–3197.

    Article  PubMed  CAS  Google Scholar 

  31. Choudhary C, Schwable J, Brandts C, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences in comparison to Flt3 ITD mutations.Blood. 2005;106:265–273.

    Article  PubMed  CAS  Google Scholar 

  32. Grundler R, Miething C, Thiede C, Peschel C, Duyster J. FLT3-ITD and tyrosine kinase domain mutants induce two distinct pheno-types in a murine bone marrow transplant model.Blood. 2005;105:4792–4799.

    Article  PubMed  CAS  Google Scholar 

  33. Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.Blood. 2002;100:59–66.

    Article  CAS  PubMed  Google Scholar 

  34. Beghini A, Peterlongo P, Ripamonti CB, et al. C-kit mutations in core binding factor leukemias.Blood. 2000;95:726–727.

    PubMed  CAS  Google Scholar 

  35. Care RS, Valk PJ, Goodeve AC, et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias.Br J Haematol. 2003;121:775–777.

    Article  PubMed  CAS  Google Scholar 

  36. Shih LY, Huang CF, Wu JH, et al. Internal tandem duplication ofFLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse.Blood. 2002;100:2387–2392.

    Article  PubMed  CAS  Google Scholar 

  37. Moreno I, Martin G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia.Haematologica. 2003;88:19–24.

    PubMed  CAS  Google Scholar 

  38. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.Blood. 2001;98:1752–1759.

    Article  PubMed  CAS  Google Scholar 

  39. Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients.Hematol J. 2003;4:41–46.

    Article  PubMed  Google Scholar 

  40. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activatingFLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm.Blood. 2002;100:4372–4380.

    Article  CAS  PubMed  Google Scholar 

  41. Liang DC, Shih LY, Hung IJ, et al. Clinical relevance of internal tandem duplication of theFLT3 gene in childhood acute myeloid leukemia.Cancer. 2002;94:3292–3298.

    Article  CAS  PubMed  Google Scholar 

  42. Weiss A, Schlessinger J. Switching signals on or off by receptor dimerization.Cell. 1998;94:277–280.

    Article  PubMed  CAS  Google Scholar 

  43. Turner AM, Lin NL, Issarachai S, Lyman SD, Broudy VC. FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells.Blood. 1996;88:3383–3390.

    PubMed  CAS  Google Scholar 

  44. Griffith J, Black J, Faerman C, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.Mol Cell. 2004;13:169–178.

    Article  CAS  PubMed  Google Scholar 

  45. Mol CD, Dougan DR, Schneider TR, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.J Biol Chem. 2004;279:31655–31663.

    Article  PubMed  CAS  Google Scholar 

  46. Mol CD, Lim KB, Sridhar V, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation.J Biol Chem. 2003; 278:31461–31464.

    Article  PubMed  CAS  Google Scholar 

  47. Schmidt-Arras DE, Bohmer A, Markova B, Choudhary C, Serve H, Bohmer FD. Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases.Mol Cell Biol. 2005;25:3690–3703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Minami Y, Kiyoi H, Yamamoto Y, et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors.Leukemia. 2002;16:1535–1540.

    Article  PubMed  CAS  Google Scholar 

  49. Yao Q, Nishiuchi R, Li Q, Kumar AR, Hudson WA, Kersey JH. FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases.Clin Cancer Res. 2003;9:4483–4493.

    PubMed  CAS  Google Scholar 

  50. George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.Blood. 2005;105:1768–1776.

    Article  PubMed  CAS  Google Scholar 

  51. George P, Bali P, Cohen P, et al. Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3.Cancer Res. 2004;64:3645–3652.

    Article  PubMed  CAS  Google Scholar 

  52. Hallberg B, Rayter SI, Downward J. Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation.J Biol Chem. 1994;269:3913–3916.

    PubMed  CAS  Google Scholar 

  53. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.Cell. 1993;73:611–620.

    Article  PubMed  CAS  Google Scholar 

  54. Johnson GL, Vaillancourt RR. Sequential protein kinase reactions controlling cell growth and differentiation.Curr Opin Cell Biol. 1994;6:230–238.

    Article  PubMed  CAS  Google Scholar 

  55. Kiyoi H, Ohno R, Ueda R, Saito H, Naoe T Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain.Oncogene. 2002;21:2555–2563.

    Article  PubMed  CAS  Google Scholar 

  56. Marchetto S, Fournier E, Beslu N, et al. SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor.Leukemia. 1999;13:1374–1382.

    Article  PubMed  CAS  Google Scholar 

  57. Rottapel R,Turck CW, Casteran N, et al. Substrate specificities and identification of a putative binding site for P13K in the carboxy tail of the murine Flt3 receptor tyrosine kinase.Oncogene. 1994;9:1755–1765.

    PubMed  CAS  Google Scholar 

  58. Zhang S, Broxmeyer HE. p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells.Biochem Biophys Res Commun. 1999;254:440–445.

    Article  PubMed  CAS  Google Scholar 

  59. Cantley LC. The phosphoinositide 3-kinase pathway.Science. 2002; 296:1655–1657.

    Article  PubMed  CAS  Google Scholar 

  60. Jonsson M, Engstrom M, Jonsson JI. FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO3.Biochem Biophys Res Commun. 2004;318:899–903.

    Article  PubMed  CAS  Google Scholar 

  61. Scheijen B, Ngo HT, Kang H, Griffin JD. FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins.Oncogene. 2004;23:3338–3349.

    Article  PubMed  CAS  Google Scholar 

  62. Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs.Proc Natl Acad Sci U S A. 2004;101:3130–3135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Blume-Jensen P, Hunter T. Oncogenic kinase signalling.Nature. 2001;411:355–365.

    Article  PubMed  CAS  Google Scholar 

  64. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation ofJAK2 in myeloproliferative disorders.N Engl J Med. 2005;352:1779–1790.

    Article  CAS  PubMed  Google Scholar 

  65. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombo-cythemia, and myeloid metaplasia with myelofibrosis.Cancer Cell. 2005;7:387–397.

    Article  PubMed  CAS  Google Scholar 

  66. James C, Ugo V, Le Couedic JP, et al. A unique clonalJAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005;434:1144–1148.

    Article  PubMed  CAS  Google Scholar 

  67. Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias.Blood. 2003; 101:2940–2954.

    Article  PubMed  CAS  Google Scholar 

  68. Gouilleux-Gruart V, Gouilleux F, Desaint C, et al. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients.Blood. 1996;87:1692–1697.

    PubMed  CAS  Google Scholar 

  69. Spiekermann K, Bagrintseva K, Schwab R, Schmieja K, Hiddemann W. Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells.Clin Cancer Res. 2003;9:2140–2150.

    PubMed  CAS  Google Scholar 

  70. Zhang S, Fukuda S, Lee Y, et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3- dependent signaling.J Exp Med. 2000;192:719–728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Laouar Y, Welte T, Fu XY, Flavell RA. STAT3 is required for Flt3L-dependent dendritic cell differentiation.Immunity. 2003;19:903–912.

    Article  PubMed  CAS  Google Scholar 

  72. Tse KF, Mukherjee G, Small D. Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation.Leukemia. 2000;14:1766–1776.

    Article  PubMed  CAS  Google Scholar 

  73. Murata K, Kumagai H, Kawashima T, et al. Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3).J Biol Chem. 2003;278:32892–32898.

    Article  CAS  PubMed  Google Scholar 

  74. Mizuki M, Schwable J, Steur C, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.Blood. 2003;101:3164–3173.

    Article  PubMed  CAS  Google Scholar 

  75. Kim KT, Baird K, Ahn JY, et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival.Blood. 2005;105:1759–1767.

    Article  PubMed  CAS  Google Scholar 

  76. Bachmann M, Hennemann H, Xing PX, Hoffmann I, Moroy T. The oncogenic serine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): a novel role for Pim-1 at the G2/M cell cycle checkpoint.J Biol Chem. 2004;279:48319–48328.

    Article  PubMed  CAS  Google Scholar 

  77. Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB. Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival.Blood. 2005;105:4477–4483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Yan B, Zemskova M, Holder S, et al. The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death.J Biol Chem. 2003;278:45358–45367.

    Article  PubMed  CAS  Google Scholar 

  79. Schuringa JJ, Chung KY, Morrone G, Moore MA. Constitutive activation of STAT5A promotes human hematopoietic stem cell self-renewal and erythroid differentiation.J Exp Med. 2004;200:623–635.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Moriggl R, Sexl V, Kenner L, et al. Stat5 tetramer formation is associated with leukemogenesis.Cancer Cell. 2005;7:87–99.

    Article  PubMed  CAS  Google Scholar 

  81. Chung KY, Morrone G, Schuringa JJ, Wong B, Dorn DC, Moore MA. Enforced expression of anFlt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis.Blood. 2005;105:77–84.

    Article  PubMed  CAS  Google Scholar 

  82. Dosil M, Wang S, Lemischka IR. Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells.Mol Cell Biol. 1993;13:6572–6585.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Robinson LJ, Xue J, Corey SJ. Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations.Exp Hematol. 2005;33:469–479.

    Article  PubMed  CAS  Google Scholar 

  84. Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells.J Leukoc Biol. 1999;65:372–380.

    Article  PubMed  CAS  Google Scholar 

  85. Zhang S, Broxmeyer HE. Flt3 ligand induces tyrosine phosphorylation of Gab1 and Gab2 and their association with Shp-2, Grb2, and PI3 kinase.Biochem Biophys Res Commun. 2000;277:195–199.

    Article  PubMed  CAS  Google Scholar 

  86. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates.Leukemia. 1998;12:301–310.

    Article  PubMed  CAS  Google Scholar 

  87. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O. The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells.J Biol Chem. 1998;273:14962–14967.

    Article  PubMed  CAS  Google Scholar 

  88. Friedman AD. Transcriptional regulation of granulocyte and monocyte development.Oncogene. 2002;21:3377–3390.

    Article  PubMed  CAS  Google Scholar 

  89. Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations ofCEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia.Nat Genet. 2001;27:263–270.

    Article  PubMed  CAS  Google Scholar 

  90. Mueller BU, Pabst T, Osato M, et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia.Blood. 2002;100:998–1007.

    Article  PubMed  CAS  Google Scholar 

  91. Dahl R, Simon MC. The importance of PU.1 concentration in hematopoietic lineage commitment and maturation.Blood Cells Mol Dis. 2003;31:229–233.

    Article  PubMed  CAS  Google Scholar 

  92. Rosenbauer F, Wagner K, Kutok JL, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.Nat Genet. 2004;36:624–630.

    Article  PubMed  CAS  Google Scholar 

  93. Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPa expression.Blood. 2004;103:1883–1890.

    Article  PubMed  CAS  Google Scholar 

  94. Zheng R, Friedman AD, Small D. Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations.Blood. 2002;100:4154–4161.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Hematology/Oncology and the Interdisciplinary Center for Clinical Research, University of Münster, Albert-Schweitzer-Strasse 33, 48129, Münster, Germany

    Chunaram Choudhary, Carsten Müller-Tidow, Wolfgang E. Berdel & Hubert Serve

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  1. Chunaram Choudhary
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Choudhary, C., Müller-Tidow, C., Berdel, W.E. et al. Signal Transduction of Oncogenic Flt3. Int J Hematol 82, 93–99 (2005). https://doi.org/10.1532/IJH97.05090

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