Normal and oncogenic FLT3

Cellular and Molecular Life Sciences

Volumn 61, Issue 23, 2004, Pages 2932-2938

  Naoe, T ^a   Kiyoi, H ^a  

^a NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

FLT3; Hematopoiesis; Kinase inhibitor; Leukemia; Point mutation; Tandem duplication; Target therapy; Tyrosine kinase

Indexed keywords

4 [6 METHOXY 7 [3 (1 PIPERIDINYL)PROPOXY] 4 QUINAZOLINYL] 1 PIPERAZINECARBOXYLIC ACID (4 ISOPROPOXYPHENYL)AMIDE; CEP 701; FLT3 LIGAND; IMATINIB; MIDOSTAURIN; SUNITINIB; TYROSINE KINASE RECEPTOR;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; BONE MARROW; CARDIOTOXICITY; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURFACE; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; ENZYME ACTIVITY; GENE DUPLICATION; GENE MUTATION; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HUMAN; LIGAND BINDING; LUNG EDEMA; MOLECULAR DYNAMICS; NONHUMAN; ONCOGENE; PROGNOSIS; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; STROMA CELL;

ANIMALS; CELL DIFFERENTIATION; CELL PROLIFERATION; COS CELLS; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA; LEUKEMIA, MYELOCYTIC, ACUTE; LIGANDS; MICE; MICE, TRANSGENIC; MODELS, MOLECULAR; MUTATION; NEOPLASMS; PHENOTYPE; POINT MUTATION; PROGNOSIS; PROTEIN STRUCTURE, TERTIARY; PROTEIN-TYROSINE KINASES; PROTO-ONCOGENE PROTEINS; RECEPTOR PROTEIN-TYROSINE KINASES; RNA, MESSENGER; STEM CELLS; TRANSFECTION;

EID: 12144279435     PISSN: 1420682X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00018-004-4274-x     Document Type: Review

References (69)

1. Mathews W., Jordan C. T., Wiegand G. W., Pardoll D. and Lemischka I. R. (1991) A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65: 1143-1152
2. Rosnet O., Marchetto S., deLapeyriere O. and Birnbaum D. (1991) Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6: 1641-1650
3. Rosnet O., Schiff C., Pebusque M. J., Marchetto S., Tonnelle C., Toiron Y. et al. (1993) Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 82: 1110-1119
4. Maroc N., Rottapel R., Rosnet O., Marchetto S., Lavezzi C., Mannoni P., Birnbaum D. and Dubreuil P. (1993) Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 8: 909-918
5. Small D., Levenstein M., Kim E., Carow C., Amin S., Rockwell P. et al. (1994) 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. USA 91: 459-463
6. Agnes F, Shamoon B., Din C., Rosnet O., Birnbaum D. and Galibert F. (1994) Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III. Gene 145: 283-288
7. Abu-Duhier F. M., Goodeve A. C., Wilson G. A., Care R. S., Peake I. R. and Reilly J. T. (2001) Genomic structure of human FLT3: implications for mutational analysis. Br. J. Haematol. 113: 1076-1077
8. Lyman S. D. (1995) Biology of flt3 ligand and receptor. Int. J. Hematol. 62: 63-73
9. Hannum C., Culpepper J., Campbell D., McClanahan T, Zurawski S., Bazan J. F. et al. (1994) Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 368: 643-648
10. Solanilla A., Grosset C., Duchez P., Legembre P., Pitard V, Dupouy M. et al. (2003) Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism. Br. J. Haematol. 120: 782-786
11. Scott L. M., Priestley G. V. and Papayannopoulou T. (2003) Deletion of alpha4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol. Cell. Biol. 23: 9349-9360
12. Mackarehtschian K., Hardin J. D., Moore K. A., Boast S., Goff S. P. and Lemischka I. R. (1995) Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3: 147-161
13. Lyman S. D. and Jacobsen S. E. (1998) c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 15: 1101-1134
14. McKenn H. J., Stocking K. L., Miller R. E., Brasel K., De Smedt T., Maraskovsky E. et al. (2000) Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells and natural killer cells. Blood 95: 3489-3497
15. Hawley T. S., Fong A. Z., Griesser H., Lyman S. D. and Hawley R. G. (1998) Leukemic predisposition of mice transplanted with gene-modified hematopoietic precursors expressing flt3 ligand. Blood 92: 2003-2011
16. Birg F., Courcoul M., Rosnet O., Bardin F., Pebusque M. J., Marchetto S. et al. (1992) Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood 80: 2584-2593
17. Drexler H. G. (1996) Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia 10: 588-599
18. Carow C. E., Levenstein M., Kaufmann S. H., Chen J., Amin S., Rockwell P. et al. (1996) Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87: 1089-1096
19. Quentmeier H. and Drexler H. G. (1996) Effects of FLT3 ligand on human leukemia cells. I. Proliferative response of myeloid leukemia cells. Leukemia 10: 261-270
20. Ozeki K., Kiyoi H., Hirose Y., Iwai M., Ninomiy M., Kodera Y. et al. (2004) Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 103: 1901-1908
21. Nakao M., Yokota S., Iwai T., Kaneko H., Horiike S., Kashima K. et al. (1996) Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10: 1911-1918
22. Kiyoi H., Naoe T., Yokota S., Nakao M., Minami S., Kuriyama K. et al. (1997) Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia 11: 1447-1452
23. Kiyoi H., Naoe T., Nakano Y., Yokota S., Minami S., Miyawaki S. et al. (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93: 3074-3080
24. Abu-Duhier F. M., Goodeve A. C., Wilson G. A., Gari M. A., Peake I. R., Rees D. C. et al. (2000) FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br. J. Haematol. 111: 190-195
25. Kottaridis P. D., Gale R. E., Frew M. E., Harrison G., Langabeer S. E., Belton. A. A. et al. (2001) 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 98: 1752-1759
26. Frohling S., Schlenk R. F., Breitruck J., Benner A., Kreitmeier S., Tobis K. et al. (2002) Prognostic significance of activating FLT3 mutations in younger adults (16-60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100: 4372-4380
27. Thiede C., Steudel C., Mohr B., Schaich M., Schakel U., Platzbecker U. et al. (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99: 4326-4335
28. Schnittger S., Schoch C., Dugas M., Kern W., Staib P., Wuchter C. et al. (2002) 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 100: 59-66
29. Horiike S., Yokota S., Nakao M., Iwai T., Sasai Y., Kaneko H. et al. (1997) Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 11: 1442-1446
30. Nakano Y., Kiyoi H., Miyawaki S., Asou N., Ohno R., Saito H. et al. (1999) Molecular evolution of acute myeloid leukaemia in relapse: unstable N-ras and FLT3 genes compared with p53 gene. Br. J. Haematol. 104: 659-664
31. Yokota S., Kiyoi H., Nakao M., Iwai T., Misawa S., Okuda T. et al. (1997) 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 11: 1605-1609
32. Xu F., Taki T., Yang. H. W., Hanada R., Hongo T., Ohnishi H. et al. (1999) Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br. J. Haematol. 105: 155-162
33. Kiyoi H., Towatari M., Yokota S., Hamaguchi M., Ohno R., Saito H. et al. (1998) Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 12: 1333-1337
34. Libura M., Asnafi V., Tu A., Delabesse E., Tigaud I., Cymbalista F., Bennaceur-Griscelli A. et al. (1997) FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. Blood 102: 2198-2204
35. Hayakawa F., Towatari M., Kiyoi H., Tanimoto M., Kitamura T., Saito H. et al. (2000) Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19: 624-631
36. Mizuki M., Fenski R., Halfter H., Matsumura I., Schmidt R., Muller C. et al. (2000) Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 96: 3907-3914
37. Kiyoi H., Ohno R., Ueda R., Saito H. and Naoe T. (2002) Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 21: 2555-2563
38. Tse K. F., Allebach J., Levis M., Smith B. D., Bohmer F. D. and Small D. (2002) Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 16: 2027-2036
39. Minami Y., Yamamoto K., Kiyoi H., Ueda R., Saito H. and Naoe T. (2003) Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. Blood 15: 2969-2975
40. Mizuki M., Schwable J., Steur C., Choudhary C., Agrawal S., Sargin B. et al. (2003) Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 15: 3164-3173
41. Minami Y., Kiyoi H., Yamamoto Y., Yamamoto K., Ueda R., Saito H. et al. (2002) Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 16: 1535-1540
42. Gilliland D. G. and Griffin J. D. (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 100: 1532-1542
43. Griffith J., Black J., Faerman C., Swenson L., Wynn M., Lu F. et al. (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell. 30: 169-178
44. Stirewalt D. L., Meshinchi S., Kussick S. J., Sheets K. M., Pogosova-Agadjanyan E., Willman C. L. et al. (2004) Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia. Br. J. Haematol. 124: 481-484
45. Zhao M., Kiyoi H., Yamamoto Y., Ito M., Towatari M., Omura S. et al. (2000) In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14: 374-378
46. Kelly L. M., Liu Q., Kutok J. L., Williams I. R., Boulton C. L. and Gilliland D. G. (2002) FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 99: 310-318
47. Kelly L. M., Kutok J. L., Williams I. R., Boulton C. L., Amaral S. M., Curley D. P. et al. (2002b) PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad of Sci USA 99: 8283-8288
48. Noguera N. I., Breccia M., Divona M., Diverio D., Costa V., De Santis S. et al. (2002) Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16: 2185-2189
49. Deguchi K. and Gilliland D. G. (2002) Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML. Leukemia 16: 740-744
50. Yamamoto Y, Kiyoi H., Nakano Y., Suzuki R., Kodera Y., Miyawaki. S. et al. (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97: 2434-2439
51. Schnittger S., Boell I., Schoch C., Dugas M., Kern. W, Sauerland M. C. et al. (2002b) FLT3D835/I836 point mutations in acute myeloid leukemia: correlation to cytogenetics, cytomorphology and prognosis in 1229 patients. Blood 100: 329a
52. Spiekermann K., Bagrintseva K., Schoch C., Haferlach T., Hiddemann W. and Schnittger. S. (2002) A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood 100: 3423-3425
53. Whitman S. P., Archer K. J., Feng L., Baldus C., Becknell B., Carlson B. D. et al. (2001) 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 Research 61: 7233-7239
54. Gallagher R. E., Lee S. J., Sankoorikal B. J., Wiernik P. H. and Tallman M. S. (2002) Independent prognostic significance of FLT3 internal tandem duplication (ITD) mutations in acute promyelocytic leukemia (APL) patients treated on ECOG protocol E2491. Blood 100: 326a
55. Palumbo G. A., Tanteri V., Buglio. D., Guagliardo P., Romeo M. A., Di Raimondo. F. et al. (2002) FLT3-activating mutations in acute promyelocytic leukemia: higher incidence of ITD in BCR3 patients. Blood 100: 326a
56. Armstrong S. A., Staunton J. E., Silverman L. B., Pieters R., den Boer M. L., Minden M. D. et al. (2002) MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30: 41-47
57. Taketani T., Taki T., Sugita K., Furuichi Y., Ishii E., Hanada R. et al. (2004) FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood 103: 1085-1088
58. Stirewalt D. L., Kopecky K. J., Meshinchi S., Appelbaum F. R., Slovak M. L., Willman C. L. et al. (2001) FLT3, RAS and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97: 3589-3595
59. Naoe T., Kiyoi H., Yamamoto Y., Minami Y., Yamamoto K., Ueda R. et al. (2001) FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. Cancer Chemother. Pharmacol. 48: S27-S30
60. Sawyers C. L. (2002) Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell. 1: 413-415
61. Stirewalt D. L. and Radich J. P. (2003) The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer 3: 650-665
62. Kelly L. M., Yu J. C., Boulton C. L., Apatira M., Li J., Sullivan C. M. et al. (2002) CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 1: 421-432
63. De Angelo. D. J., Stone R. M., Bruner R. J., Caligiuri M. A., Heaney M. L., Nimer S. D. et al. (2003) Phase I clinical results with MLN518, a novel FLT3 antagonist: tolerability, pharmacokinetics and pharmacodynamics. Blood 102: 65a-66a
64. Weisberg E., Boulton C., Kelly L. M., Manley P., Fabbro. D., Meyer T. et al. (2002) Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1: 433-443
65. Stone R. M., Klimek V., DeAngelo D. J., Nimer S., Estey E., Galinsky I. et al. (2002) PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood 100: 86a
66. Levis M., Tse K. F., Smith B. D., Garrett E. and Small D. (2001) A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 98: 885-887
67. Smith B. D., Levis M., Beran M., Giles F., Kantarjian H., Berg K. et al. (2004) Single agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103: 3669-3676
68. O'Farrell A. M., Abrams T. J., Yuen H. A., Ngai T. J., Louie S. G., Yee K. W. et al. (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101: 3597-3605
69. Fiedler W., Serve H., Döhner H., Niederwieser D., Ottmann O. G., O'Farrell M. et al. (2003) A Phase I study of SU11248 in the treatment of patients with acute myeloid leukemia (AML) refractory or resistant or not amenable to conventional therapy. Blood 102: 616a