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Open Access Green as soon as Postprint is submitted to ZB.
FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L).
Blood 105, 3679-3685 (2005)
FLT3 (fms-like tyrosine kinase 3) is constitu-
tively activated in about 30% of patients with
acute myeloid leukemia (AML) and repre-
sents a disease-specific molecular marker.
Although FLT3-LM (length mutation) and
TKD (tyrosine kinase domain) mutations
have been considered to be mutually exclu-
sive, 1% to 2% of patients carry both muta-
tions. However, the functional and clinical
significance of this observation is unclear.
We demonstrate that FLT3-ITD-TKD dual mu-
tants induce drug resistance toward PTK
inhibitors and cytotoxic agents in in vitro
model systems. As molecular mechanisms
of resistance, we found that FLT3-ITD-TKD
mutants cause hyperactivation of STAT5
(signal transducer and activator of transcrip-
tion-5), leading to upregulation of Bcl-x(L)
and RAD51 and arrest in the G
2
M phase of
the cell cycle. Overexpression of Bcl-x(L)
was identified as the critical mediator of
drug resistance and recapitulates the PTK
inhibitor and daunorubicin-resistant pheno-
type in FLT3-ITD cells. The combination of
rapamycin, a selective mTOR inhibitor, and
FLT3 PTK inhibitors restored the drug sensi-
tivity in FLT3 dual mutant–expressing cells.
Our data provide the molecular basis for
understanding clinical FLT3 PTK inhibitor
resistance and point to therapeutical strate-
gies to overcome drug resistance in pa-
tients withAML.
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Publication type
Article: Journal article
Document type
Scientific Article
ISSN (print) / ISBN
0006-4971
e-ISSN
1528-0020
Journal
Blood
Quellenangaben
Volume: 105,
Issue: 9,
Pages: 3679-3685
Publisher
American Society of Hematology
Reviewing status
Peer reviewed