An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: Biology and treatment

Oncology Reviews

Volumn 6, Issue 1, 2012, Pages 64-74

  Grafone, Tiziana ^a   Palmisano, Michela ^b   Nicci, Chiara ^a   Storti, Sergio ^a  

^a Fondazione di Ricerca e Cura Giovanni Paolo II   (Italy)

^b VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

Author keywords

Acute myeloid leukemia; FLT3 receptor; Inhibitors; Internal tandem duplication; Signal transduction networks

Indexed keywords

CD135 ANTIGEN; FLT3 LIGAND; PROTEIN TYROSINE KINASE; TRANSCRIPTION FACTOR; TYROSINE KINASE RECEPTOR;

ACUTE GRANULOCYTIC LEUKEMIA; APOPTOSIS; CELL PROLIFERATION; HUMAN; LEUKEMOGENESIS; MOLECULAR THERAPY; PHOSPHOLIPID METABOLISM; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

EID: 84878638746     PISSN: 19705557     EISSN: 19705565     Source Type: Journal    
DOI: 10.4081/oncol.2012.e8     Document Type: Review

References (111)

1. Irons RD, Stillman WS. The process of leukemogenesis. Environ Health Perspect 1996; 104:1239-46.
2. Gilliland GD. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol 2002; 39:6-11.
3. Motyckova G, Stone RM. The role of molecular tests in acute myel-ogenous leukemia treatment decisions. Curr Hematol Malig Rep 2010; 5:109-117.
4. Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004:80-97.
5. Vardiman JW, Thiele J, Arber D, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukaemia: rationale and important changes. Blood 2009; 114:937-51.
6. Rosnet O, Mattei MG, Marchetto S, Birnbaum D. Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene. Genomics 1991; 9:380-5.
7. 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; 70:255-7.
8. Rosnet O. FLT3 (Fms-like tyrosine kinase3). Atlas Genet Cytogenet Oncol Haematol 1999; 3:73-4.
9. Agnes F, Shamoon B, Dina C, et al. Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among gene encoding receptor tyrosine kinases (RTK) of subclass III. Gene 1994; 145:283-8.
10. Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Genomic structure of human FLT3: implications for mutational analysis. Br J Haematol 2001; 113:1076-7.
11. Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 1993; 82:1110-9.
12. Griffith J, Black J, Faerman L, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 2004; 13:169-78.
13. Lyman SD, Jacobsen SE. c-kit ligand and flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91:1101-34.
14. Markovic A, Mackenzie KL, Lock RB. FLT3: a new focus in the understanding of acute leukemia. Int J Biochem Cell Biol 2005; 37: 1168-72.
15. Rosnet O, Buhring HJ, Marchetto S, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 1996; 10:238-48.
16. 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; 8:909-18.
17. Kikushige Y, Yoshimoto G, Miyamoto T, et al. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol 2008; 180:7358-67.
18. Kindler T, Lipka DB, Fisher T. FLT3 as a therapeutic target in AML: still changes after all these years. Blood 2010; 116:5089-102.
19. Gotze K, Ramirez M, Tabor K, et al. Flt3 high and Flt3 low CD34+ progenitor cell isolated from human bone marrow are functionally distinct. Blood 1998; 91:1947-58.
20. Stirewalt DL, Radich J P. The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer 2003; 3:650-65.
21. Del Zotto G, Luchetti F, Zamai L. CD135. J Biol Regul Homeost Agents 2001; 15:103-16.
22. Brown P, Small D. FLT3 inhibitors: a paradigm of the development of targeted therapeutics for pediatric cancer. Eur J Cancer 2004; 40:707-21.
23. Cheetham GM. Novel protein kinases and molecular mechanisms of autoinhibition. Curr Opin Struct Biol 2004; 14:700-5.
24. Lyman SD. Biology of flt3 ligand and receptor. Int J Hematol 1995; 62:63-73.
25. Wodnar-Filipowicz A. FLT3 ligand: role in control of hematopoietic and immune functions of the bone marrow. News Physiol Sci 2003; 18:247-51.
26. Lisovsky M, Braun SE, Ge Y, et al. Flt3-ligand production by human bone marrow stromal cells. Leukemia 1996; 10:1012-8.
27. Lyman SD, James L, Vanden Bos T, et al. Molecular cloning of a lig-and for the flt3/flk-2 tyrosine kKinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75:1157-67.
28. Lyman SD, James L, Johnson L, et al. Cloning of the human homo-logue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 1994; 83:2795-801.
29. Yonemura Y, Ku H, Lyman SD, Ogawa M. In vitro expansion of hematopoietic progenitors and maintenance of stem cells: comparison between FLT3/FLK-2 ligand and KIT ligand. Blood 1997; 89: 1915-21.
30. Gilliland GD, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100:1532-42.
31. Jönsson M, Engström M, Jönsson JI. FLT3 Ligand regulates apop-tosis through AKT-dependent inactivation of transcription factor FoxO3. Biochem Biophys Res Commun 2004; 318:899-903.
32. Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 2004; 103:267-74.
33. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001; 93:1062-74.
34. Scholl C, Gilliland DG, Frohling S. Deregulation of signaling pathways in acute myeloid leukemia. Semin Oncol 2008; 35:336-45.
35. 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; 65:372-80.
36. Marchetto S, Fournier E, Beslu N, et al. SHC and SHIP phosphory-lation and interaction in response to activation of the FLT3 receptor. Leukemia 1999; 13:1374-82.
37. Zhang S, Broxmeyer HE. Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp2, grb2 and PI3 kinase. Biochem Biophys Res Commun 2000; 277:195-9.
38. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phos-phatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 2010; 1:89-103.
39. Altmann JK, Sassano A, Platanias LC. Targeting mTor for the treatment of AML. New agents and new directions. Oncotarget 2011; 2: 510-7.
40. Kim KT, Levis M, Small D. Constitutively activated FLT3 phospho-rylates BAD partially through pim1. Br J Haematol 2006; 134:500-9.
41. Xu Q, Simpson SE, Scialla TJ, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003; 102:972-80.
42. Yang JY, Hung MC. A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin Cancer Res 2009; 15: 752-7.
43. Zhang Y, Gan B, Liu D, Paik J. FOXO family member in cancer. Cancer Biol Ther 2011; 12:253-9.
44. Kottaridis PD, Gale RE, Linch DC. FLT3 mutations and leukaemia. Br J Hematol 2003; 122:523-38.
45. Martinelli G, Piccaluga PP, Lo Coco F. FLT3 Inhibition as tailored therapy for acute myeloid leukemia. Haematologica 2003; 88:4-8.
46. Dasilva N, Hu ZB, Ma W, et al. Expression of the FLT3 gene in human-lymphoma cell lines Leukemia 1994; 8:885-8.
47. Meierhoff G, Dehmel U, Gruss HJ, et al. Expression of the FLT3 receptor and FLT3 ligand in human leukemia-lymphoma cell lines. Leukemia 1995; 9:1368-72.
48. Fenski R, Flesch K, Serve S, et al. Costitutive activation of FLT3 in acute myeloid leukemia and its consequences for growth of 32D cells. Br J Haematol 2000; 108:322-30.
49. Bruserud O, Hovland R, Wergeland L, et al. Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand the effects in AML cell populations with and without genetic Flt3 abnormalities. Haematologica 2003; 88:416-28.
50. Bianchini M, Ottaviani E, Grafone T, et al. Rapid detection of Flt3 mutations in acute myeloid leukemia patients by denaturing HPLC. Clin Chem 2003; 49:1642-50.
51. Piccaluga PP, Bianchini M, Martinelli G. Novel FLT3 point mutation in acute myeloid leukaemia. Lancet Oncol 2003; 4:604.
52. Sritana N, Auewarakul C. KIT and FLT3 receptor tyrosine kinase mutations in acute myeloid leukaemia with favorable cytogenet-ics: two novel mutations and selective occurrence in leukaemia subtypes and age groups. Exp Mol Pathol 2008; 85:227-31.
53. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the gene flt3 found in acute myeloid leukemia. Leukemia 1996; 10: 1911-8.
54. Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood 2009; 113:4074-7.
55. 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; 107:3700-7.
56. Gianfelici V, Diverio D, Breccia M, et al. A novel point mutation within the juxtamembrane domain of the FLT3 gene in acute myeloid leukemia. Ann Hematol 2010; 90:845-6.
57. Chung KY, Morrone G, Schuringa JJ, et al. Enforced expression of a Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis. Blood 2005; 105:77-84.
58. 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; 19:624-31.
59. Yonemura Y, Ku H, Lyman SD, Ogawa M. In vitro expansion of hematopoietic progenitors and maintenance of stem cells: comparison between FLT3/FLK-2 ligand and KIT ligand. Blood 1997; 89: 1915-21.
60. 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; 105:1759-67.
61. Takahashi S, Harigae H, Kaku M, et al. FLT3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5. Biochem Biophys Res Commun 2004; 316:85-92.
62. Nosaka T, Kawashima T, Misawa K, et al. STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J 1999; 18:4754-65.
63. 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; 96:3907-14.
64. Spiekermann K, Bagrintseva K, Schwab R, et al. Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clin Cancer Res 2003; 9:2140-50.
65. Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J Hematol Oncol 2011; 4:13.
66. 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; 23:3338-49.
67. Zheng R, Friedman AD, Levis M, et al. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBP expression. Blood 2004; 103:1883-90.
68. Chen P, Levis M, Brown P, et al. FLT3/ITD Mutation signaling includes suppression of SHP-1. J Biol Chem 2005; 280:5361-9.
69. Tickenbrock L, Schwäble J, Wiedehage M, et al. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 2005; 105:3699-706.
70. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97:2434-9.
71. Sholl S, Krause C, Loncarevic IF, et al. Specific detection of FLT3 point mutations by highly sensitive real time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med 2005; 145:295-304.
72. Jiang J, Paez JG, Lee JC, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML. Blood 2004; 104:1855-8.
73. Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001; 113:983-8.
74. Choudhary C, Schwable J, Brandts C, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with ITD mutations. Blood 2005; 106:265-73.
75. Kottaridis PD, GaleRE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytoge-netic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98:1752-9.
76. 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.
77. 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; 99:4326-35.
78. Levis M, Small D. ITDoes matter leukemia 2003; 17:1738-52.
79. Au WY, Fung A, Chim CS, et al. FLT3 aberrations in acute promye-locytic leukaemia: clinicopathological associations and prognostic impact. Br J Haematol 2004; 125:463-9.
80. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61:7233-9.
81. Shih LY, Lin TL, Wang PN, et al. Internal tandem duplication of Fms-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome. Cancer 2004; 101:989-98.
82. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010; 116:5089-102.
83. Griffin DJ. Point mutations in the FLT3 gene in AML. Blood 2001; 97:2193.
84. Carnicer MJ, Nomdedeu JF, Lasa A, et al. FLT3 mutations are associated with other molecular lesions in AML. Leuk Res 2004; 28:19-23.
85. Bagrintseva K, Schwab R, Kohl TM, et al. Mutations in the tyro-sine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-trans-formed hematopoietic cells. Blood 2004; 103:2266-75.
86. 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; 106:265-73.
87. Bagrintseva K, Geisenhof S, Kern R, et al. FLT3-ITD-TKD dual mutants associated AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L). Blood 2005; 105:3679-85.
88. Tiesmeier J, Muller-Tidow C, Westermann A, et al. Evolution of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and response to salvage therapy. Leuk Res 2004; 28:1069-74.
89. Zwaan CM, Kaspers GJ. Possibilities for tailored and targeted therapy in pediatric acute myeloid leukaemia. Br J Hematol 2004; 127: 264-79.
90. Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 2002; 1:413-5.
91. Shabbir M, Stuart R. Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside. Expert Opin Invest Drugs 2010; 19:427-36.
92. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chempotherapy. Blood 2006; 108:3262-70.
93. Fathi A, Chen YB. Treatment of FLT3-ITD acute myeloid leukemia. Am J Blood Res 2011; 1:175-89.
94. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvatage chemotherapy followed by lestaurtinib for patients with FLT3 mutant in AML in first relapse. Blood 2011; 117:3294-301.
95. Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacoki-netic study of PK412, an inhibitor of protein kinase C. J Clin Oncol 2001; 19:1485-92.
96. Fisher T, Stone MR, DeAngelo DJ, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28:4339-45.
97. Stölzel F, Steudel C, Oelschlägel U, et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol 2010; 89:653-62.
98. Wilhelm S, Carter C, Tang L, et al. Bay 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64:7099-109.
99. Wilhelm S, Adnane L, Newell P, et al. Preclinical overwiev of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signalling. Mol Cancer Ther 2008; 7:3129-40.
100. Zhang W, Konopleva M, Ruvolo VR, et al. Sorafenib induces apop-tosis of AML cells via Bim-mediated activation of intrinsecapoptot-ic pathway. Leukemia 2008; 22:808-18.
101. Zhang W, Konopleva M, Shi Y, et al. Mutant FLT3: a direct target of sorafenib in AML. J Natl Cancer Inst 2008; 100:184-98.
102. Pemmaraju N, Kantarjian H, Ravandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia. Cancer 2011; 117:3293-304.
103. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28:1856-60.
104. Fathi A, Lewis M. Flt3 inhibitors: a story of the old and the new. Curr Opin Hematol 2011; 18:71-6.
105. Zarrinkar P P, Gunawardane RN, Cramer Gardner MF, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114:2984-92.
106. Cortes J, Foran J, Ghirdaladze D, et al. AC220, a potent, selective, second generation FLT3 receptor tyrosine kinase (RTK) inhibitor, in a firstin-human (FIH) phase 1 AML study. Blood (ASH Annual Meeting Abstracts) 2009; 114:Abstract 636.
107. Levis MA. Phase II open-label, AC220 monotherapy efficacy (ACE) study in patients with acute myeloid leukemia (AML) with FLT3-ITD activating mutations: interim results. Congress of the European Hematology Association. 2011:Abstract 1019.
108. Weisberg E, Sattler M, Ray A, Griffin JD. Drug resistance in mutant FLT3 positive AML. Oncogene 2010; 29:5120-34.
109. Grafone T, Palmisano M, Nicci C, et al. Monitoring of FLT3 phos-phorylation status and its response to drugs by flow cytometry in AML blast cells. Hematol Oncol 2008; 26:159-66.
110. Levis M. FLT3/ITD AML and the law of unintended consequences. Blood 2011; 117:6987-90.
111. Sato T, Yang X, Knapper S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 2011; 117:3286-93.