| Title |
Leukemogenic potency of the novel FLT3-N676K mutant
|
|---|---|
| Published in |
Annals of Hematology, February 2016
|
| DOI | 10.1007/s00277-016-2616-z |
| Pubmed ID | |
| Authors |
Kezhi Huang, Min Yang, Zengkai Pan, Florian H. Heidel, Michaela Scherr, Matthias Eder, Thomas Fischer, Guntram Büsche, Karl Welte, Nils von Neuhoff, Arnold Ganser, Zhixiong Li |
| Abstract |
The novel FMS-like tyrosine kinase 3 (FLT3)-N676K point mutation within the FLT3 kinase domain-1 was recently identified in 6 % of de novo acute myeloid leukemia (AML) patients with inv(16). Because FLT3-N676K was encountered almost exclusively in inv(16) AML, we investigated the transforming potential of FLT3-N676K, the cooperation between FLT3-N676K and core binding factor ß-smooth muscle myosin heavy chain (CBFß-SMMHC) (encoded by the inv(16) chimeric gene CBFB-MYH11) in inducing acute leukemia, and tested the sensitivity of FLT3-N676K-positive leukemic cells to FLT3 inhibitors. Retroviral expression of FLT3-N676K in myeloid 32D cells induced AML in syngeneic C3H/HeJ mice (n = 11/13, median latency 58 days), with a transforming activity similar to FLT3-internal tandem duplication (ITD) (n = 8/8), FLT3-TKD D835Y (n = 8/9), and FLT3-ITD-N676K (n = 9/9) mutations. Three out of 14 (21.4 %) C57BL/6J mice transplanted with FLT3-N676K-transduced primary hematopoietic progenitor cells developed acute leukemia (latency of 68, 77, and 273 days), while no hematological malignancy was observed in the control groups including FLT3-ITD. Moreover, co-expression of FLT3-N676K/CBFß-SMMHC did not promote acute leukemia in three independent experiments (n = 16). In comparison with FLT3-ITD, FLT3-N676K induced much higher activation of FLT3 and tended to trigger stronger phosphorylation of MAPK and AKT. Importantly, leukemic cells carrying the FLT3-N676K mutant in the absence of an ITD mutation were highly sensitive to FLT3 inhibitors AC220 and crenolanib, and crenolanib even retained activity against the AC220-resistant FLT3-ITD-N676K mutant. Taken together, the FLT3-N676K mutant is potent to transform murine hematopoietic stem/progenitor cells in vivo. This is the first report of acute leukemia induced by an activating FLT3 mutation in C57BL/6J mice. Moreover, further experiments investigating molecular mechanisms for leukemogenesis induced by FLT3-N676K mutation and clinical evaluation of FLT3 inhibitors in FLT3-N676K-positive AML seem warranted. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 3 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 26 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 23% |
| Student > Postgraduate | 4 | 15% |
| Other | 3 | 12% |
| Student > Bachelor | 3 | 12% |
| Student > Ph. D. Student | 3 | 12% |
| Other | 3 | 12% |
| Unknown | 4 | 15% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 12 | 46% |
| Biochemistry, Genetics and Molecular Biology | 6 | 23% |
| Nursing and Health Professions | 1 | 4% |
| Agricultural and Biological Sciences | 1 | 4% |
| Engineering | 1 | 4% |
| Other | 0 | 0% |
| Unknown | 5 | 19% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 August 2016.
All research outputs
#17,787,961
of 22,849,304 outputs
Outputs from Annals of Hematology
#1,361
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Outputs of similar age
#202,557
of 297,895 outputs
Outputs of similar age from Annals of Hematology
#10
of 24 outputs
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