Seminars in Oncology
Volume 35, Issue 4 , Pages 336-345 , August 2008

Deregulation of Signaling Pathways in Acute Myeloid Leukemia

References 

  1. Parcells BW, Ikeda AK, Simms-Waldrip T, et al. FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. Stem Cells. 2006;24:1174–1184
  2. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–665
  3. Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006;107:3700–3707
  4. Stirewalt DL, Meshinchi S, Kussick SJ, et al. Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia. Br J Haematol. 2004;124:481–484
  5. Kelly LM, Liu Q, Kutok JL, et al. 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
  6. Lee BH, Tothova Z, Levine RL, et al. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007;12:367–380
  7. Lee BH, Williams IR, Anastasiadou E, et al. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene. 2005;24:7882–7892
  8. Frohling S, Scholl C, Gilliland DG, et al. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol. 2005;23:6285–6295
  9. Choudhary C, Schwable J, Brandts C, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood. 2005;106:265–273
  10. Spiekermann K, Dirschinger RJ, Schwab R, et al. The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood. 2003;101:1494–1504
  11. Grundler R, Miething C, Thiede C, et al. FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005;105:4792–4799
  12. Rocnik JL, Okabe R, Yu JC, et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006;108:1339–1345
  13. Bagrintseva K, Schwab R, Kohl TM, et al. Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells. Blood. 2004;103:2266–2275
  14. Grundler R, Thiede C, Miething C, et al. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood. 2003;102:646–651
  15. Schittenhelm MM, Yee KW, Tyner JW, et al. FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248). Leukemia. 2006;20:2008–2014
  16. Frohling S, Scholl C, Levine RL, et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007;12:501–513
  17. Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103:1901–1908
  18. Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267–274
  19. Caligiuri MA, Briesewitz R, Yu J, et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood. 2007;110:1022–1024
  20. Sargin B, Choudhary C, Crosetto N, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007;110:1004–1012
  21. Lennartsson J, Jelacic T, Linnekin D, et al. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005;23:16–43
  22. Blume-Jensen P, Claesson-Welsh L, Siegbahn A, et al. Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J. 1991;10:4121–4128
  23. Lemmon MA, Pinchasi D, Zhou M, et al. Kit receptor dimerization is driven by bivalent binding of stem cell factor. J Biol Chem. 1997;272:6311–6317
  24. Philo JS, Wen J, Wypych J, et al. Human stem cell factor dimer forms a complex with two molecules of the extracellular domain of its receptor, Kit. J Biol Chem. 1996;271:6895–6902
  25. Gari M, Goodeve A, Wilson G, et al. c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br J Haematol. 1999;105:894–900
  26. Yuzawa S, Opatowsky Y, Zhang Z, et al. Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell. 2007;130:323–334
  27. Lemmon MA, Ferguson KM. A new twist in the transmembrane signaling tool-kit. Cell. 2007;130:213–215
  28. Kohl TM, Schnittger S, Ellwart JW, et al. KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood. 2005;105:3319–3321
  29. Beghini A, Magnani I, Ripamonti CB, et al. Amplification of a novel c-Kit activating mutation Asn(822)-Lys in the Kasumi-1 cell line: a t(8;21)-Kit mutant model for acute myeloid leukemia. Hematol J. 2002;3:157–163
  30. Beghini A, Peterlongo P, Ripamonti CB, et al. C-kit mutations in core binding factor leukemias. Blood. 2000;95:726–727
  31. Ning ZQ, Li J, Arceci RJ. Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells. Blood. 2001;97:3559–3567
  32. Ning ZQ, Li J, McGuinness M, et al. STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity. Oncogene. 2001;20:4528–4536
  33. Schwartz S, Heinecke A, Zimmermann M, et al. Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance. Leuk Lymphoma. 1999;34:85–94
  34. Wang C, Curtis JE, Geissler EN, et al. The expression of the proto-oncogene C-kit in the blast cells of acute myeloblastic leukemia. Leukemia. 1989;3:699–702
  35. Ikeda H, Kanakura Y, Tamaki T, et al. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood. 1991;78:2962–2968
  36. Pietsch T. Paracrine and autocrine growth mechanisms of human stem cell factor (c-kit ligand) in myeloid leukemia. Nouv Rev Fr Hematol. 1993;35:285–286
  37. Blume-Jensen P, Wernstedt C, Heldin CH, et al. Identification of the major phosphorylation sites for protein kinase C in kit/stem cell factor receptor in vitro and in intact cells. J Biol Chem. 1995;270:14192–14200
  38. Yee NS, Hsiau CW, Serve H, et al. Mechanism of down-regulation of c-kit receptor (Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C). J Biol Chem. 1994;269:31991–31998
  39. Lorenz U, Bergemann AD, Steinberg HN, et al. Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-Kit by the protein tyrosine phosphatase SHP1. J Exp Med. 1996;184:1111–1126
  40. Paulson RF, Vesely S, Siminovitch KA, et al. Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1. Nat Genet. 1996;13:309–315
  41. Huber M, Helgason CD, Scheid MP, et al. Targeted disruption of SHIP leads to Steel factor-induced degranulation of mast cells. EMBO J. 1998;17:7311–7319
  42. De Sepulveda P, Okkenhaug K, Rose JL, et al. Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. EMBO J. 1999;18:904–915
  43. Miyazawa K, Toyama K, Gotoh A, et al. Ligand-dependent polyubiquitination of c-kit gene product: a possible mechanism of receptor down modulation in M07e cells. Blood. 1994;83:137–145
  44. Wisniewski D, Strife A, Clarkson B. c-kit ligand stimulates tyrosine phosphorylation of the c-Cbl protein in human hematopoietic cells. Leukemia. 1996;10:1436–1442
  45. Dohner K, Du J, Corbacioglu A, et al. JAK2V617F mutations as cooperative genetic lesions in t(8;21)-positive acute myeloid leukemia. Haematologica. 2006;91:1569–1570
  46. Frohling S, Lipka DB, Kayser S, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood. 2006;107:1242–1243
  47. Illmer T, Schaich M, Ehninger G, et al. Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. Haematologica. 2007;92:137–138
  48. Levine RL, Loriaux M, Huntly BJ, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood. 2005;106:3377–3379
  49. Schnittger S, Bacher U, Kern W, et al. JAK2 seems to be a typical cooperating mutation in therapy-related t(8;21)/ AML1-ETO-positive AML. Leukemia. 2007;21:183–184
  50. Walters DK, Mercher T, Gu TL, et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell. 2006;10:65–75
  51. Cazzaniga G, Tosi S, Aloisi A, et al. The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood. 1999;94:4370–4373
  52. Soupir CP, Vergilio JA, Dal Cin P, et al. Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol. 2007;127:642–650
  53. Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol. 2005;15:R563–R574
  54. Sebti SM, Der CJ. Opinion: searching for the elusive targets of farnesyltransferase inhibitors. Nat Rev Cancer. 2003;3:945–951
  55. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–465
  56. Van Meter ME, Diaz-Flores E, Archard JA, et al. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood. 2007;109:3945–3952
  57. Bos JL, Verlaan-de Vries M, van der Eb AJ, et al. Mutations in N-ras predominate in acute myeloid leukemia. Blood. 1987;69:1237–1241
  58. Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106:2113–2119
  59. Bamford S, Dawson E, Forbes S, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer. 2004;91:355–358
  60. Bacher U, Haferlach T, Schoch C, et al. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107:3847–3853
  61. Yang G, Khalaf W, van de Locht L, et al. Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. Mol Cell Biol. 2005;25:5869–5879
  62. Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–647
  63. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia. 2006;20:911–928
  64. Platanias LC. Map kinase signaling pathways and hematologic malignancies. Blood. 2003;101:4667–4679
  65. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441:424–430
  66. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–444
  67. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954
  68. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554
  69. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999;96:4240–4245
  70. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475–482
  71. Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441:518–522
  72. Lin J, Gan CM, Zhang X, et al. A multidimensional analysis of genes mutated in breast and colorectal cancers. Genome Res. 2007;17:1304–1318
  73. Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–274
  74. Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–1113
  75. Bullinger L, Dohner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350:1605–1616
  76. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–537
  77. Radmacher MD, Marcucci G, Ruppert AS, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood. 2006;108:1677–1683
  78. Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350:1617–1628
  79. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–764
  80. Rawat VP, Thoene S, Naidu VM, et al. Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia. Blood. 2008;111:309–319
  81. Scholl C, Bansal D, Dohner K, et al. The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis. J Clin Invest. 2007;117:1037–1048
  82. Rucker FG, Bullinger L, Schwaenen C, et al. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol. 2006;24:3887–3894
  83. Marcucci G, Baldus CD, Ruppert AS, et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:9234–9242
  84. Baldus CD, Burmeister T, Martus P, et al. High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults. J Clin Oncol. 2006;24:4714–4720
  85. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–397
  86. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500
  87. Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–158
  88. Ley TJ, Minx PJ, Walter MJ, et al. A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes. Proc Natl Acad Sci U S A. 2003;100:14275–14280
  89. Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007;39:347–351
  90. Kim SY, Hahn WC. Cancer genomics: integrating form and function. Carcinogenesis. 2007;28:1387–1392
  91. Ngo VN, Davis RE, Lamy L, et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature. 2006;441:106–110
  92. Westbrook TF, Martin ES, Schlabach MR, et al. A genetic screen for candidate tumor suppressors identifies REST. Cell. 2005;121:837–848
  93. Boehm JS, Zhao JJ, Yao J, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007;129:1065–1079
  94. Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436:117–122
  95. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol. 2007;138:687–699
  96. DeAngelo DJ, Stone RM, Heaney ML, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006;108:3674–3681
  97. Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993
  98. Clark JJ, Cools J, Curley DP, et al. Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518. Blood. 2004;104:2867–2872
  99. Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433–443
  100. Knapper S, Mills KI, Gilkes AF, et al. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood. 2006;108:3494–3503
  101. Piloto O, Wright M, Brown P, et al. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood. 2006;109:1643–1652
  102. Beghini A, Bellini M, Magnani I, et al. STI 571 inhibition effect on KITAsn822Lys-mediated signal transduction cascade. Exp Hematol. 2005;33:682–688
  103. Cammenga J, Horn S, Bergholz U, et al. Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood. 2005;106:3958–3961
  104. Cairoli R, Beghini A, Morello E, et al. Imatinib mesylate in the treatment of core binding factor leukemias with KIT mutations (A report of three cases). Leuk Res. 2005;29:397–400
  105. Nanri T, Matsuno N, Kawakita T, et al. Imatinib mesylate for refractory acute myeloblastic leukemia harboring inv(16) and a C-KIT exon 8 mutation. Leukemia. 2005;19:1673–1675
  106. Gleixner KV, Mayerhofer M, Aichberger KJ, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2006;107:752–759
  107. Growney JD, Clark JJ, Adelsperger J, et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood. 2005;106:721–724
  108. Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473–481
  109. Gotlib J, Berube C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865–2870
  110. Cortes J, Giles F, O'Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer. 2003;97:2760–2766
  111. Heidel F, Cortes J, Rucker FG, et al. Results of a multicenter phase II trial for older patients with c-Kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose Ara-C and Imatinib. Cancer. 2007;109:907–914
  112. Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood. 2004;103:3644–3654
  113. Basso AD, Kirschmeier P, Bishop WR. Lipid posttranslational modifications (Farnesyl transferase inhibitors). J Lipid Res. 2006;47:15–31
  114. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109:1387–1394
  115. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22
  116. Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689–698
  117. Martelli AM, Tazzari PL, Evangelisti C, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem. 2007;14:2009–2023
  118. Milella M, Precupanu CM, Gregorj C, et al. Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects. Curr Pharm Des. 2005;11:2779–2795
  119. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358–362

PII: S0093-7754(08)00114-0

doi: 10.1053/j.seminoncol.2008.04.004

Seminars in Oncology
Volume 35, Issue 4 , Pages 336-345 , August 2008