Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines.
Fumihiko Hayakawa,Masayuki Towatari,Hitoshi Kiyoi,Mitsune Tanimoto,Toshio Kitamura,H Saito,Tomoki Naoe +6 more
TLDR
In this paper, the internal tandem duplication of the human Flt3 gene in approximately 20% of acute myeloid leukemia (AML) cases was identified, and the wild-type and the mutant FLt3 genes were transfected into two IL-3-dependent cell lines, 32D and BA/F3 cells.Abstract:
We have recently identified an internal tandem duplication of the human Flt3 gene in approximately 20% of acute myeloid leukemia (AML) cases. In the present study, the wild-type and the mutant Flt3 genes were transfected into two IL-3-dependent cell lines, 32D and BA/F3 cells. Mutant Flt3-transfected cells exhibited autonomous growth while wild-type Flt3-transfected cells with the continuous stimulation of Flt3 ligand exhibited a minimal proliferation. Cells expressing mutant Flt3 showed constitutive activation of STAT5 and MAP kinase. In contrast, Flt3 ligand stimulation caused rapid activation of MAP kinase but not STAT5 in cells expressing wild-type Flt3. Finally, we found constitutive activation of MAP kinase and STAT5 in all clinical samples of AML patients with mutant Flt3. Our study shows the significance of internal tandem duplication of Flt3 receptors for leukemia cell expansion.read more
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Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis
Christian Thiede,Christine Steudel,Brigitte Mohr,Markus Schaich,Ulrike Schäkel,Uwe Platzbecker,Martin Wermke,Martin Bornhäuser,Markus Ritter,Andreas Neubauer,Gerhard Ehninger,Thomas Illmer +11 more
TL;DR: In this paper, the authors analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 acute myelogenous leukemia (AML) patients and found that a high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.
Journal ArticleDOI
The roles of FLT3 in hematopoiesis and leukemia.
TL;DR: Results suggest that FLT3 is an attractive therapeutic target for kinase inhibitors or other approaches for patients with mutations of this gene, and preliminary studies suggest that mutantFLT3 cooperates with other leukemia oncogenes to confer a more aggressive phenotype.
Journal ArticleDOI
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.
Panagiotis D. Kottaridis,Rosemary E. Gale,Marion E. Frew,G Harrison,Stephen E. Langabeer,Andrea A. Belton,Helen Walker,Keith Wheatley,David T. Bowen,Alan Kenneth Burnett,Anthony H. Goldstone,David C. Linch +11 more
TL;DR: In this article, the impact of internal tandem duplication (ITD) in the FLT3 gene on clinical outcome was evaluated in 854 patients, mostly 60 years of age or younger, treated in the United Kingdom Medical Research Council (MRC) trials.
Journal ArticleDOI
Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.
Yukiya Yamamoto,Hitoshi Kiyoi,Yasuyuki Nakano,Ritsuro Suzuki,Yoshihisa Kodera,Shuichi Miyawaki,Norio Asou,Kazutaka Kuriyama,Fumiharu Yagasaki,Chihiro Shimazaki,Hideki Akiyama,Kenji Saito,Miki Nishimura,Toshiko Motoji,Katsuji Shinagawa,Akihiro Takeshita,Hidehiko Saito,Ryuzo Ueda,Ryuzo Ohno,Tomoki Naoe +19 more
TL;DR: Analysis of the mutation of D835 of FLT3, which corresponds to D816 of c-KIT, in a large series of human hematologic malignancies demonstrates that the FLT 3 gene is the target most frequently mutated to become constitutively active in AML.
Journal ArticleDOI
SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
Anne Marie O'Farrell,Tinya Abrams,Helene A. Yuen,Theresa J. Ngai,Sharianne G. Louie,Kevin W.H. Yee,Lily Wong,Weiru Hong,Leslie Lee,Ajia Town,Beverly D. Smolich,William C. Manning,Lesley J. Murray,Michael Heinrich,Julie M. Cherrington +14 more
TL;DR: The in vivo efficacy of SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model, suggesting that further exploration of SU 11248 activity in AML patients is warranted.
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