Journal
EXPERIMENTAL HEMATOLOGY
Volume 39, Issue 4, Pages 473-485Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2011.01.009
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Funding
- Leukemia and Lymphoma Society (White Plains, NY, USA)
- Lauri Strauss Leukemia Foundation (Port Washington, NY, USA)
- Wake Forest University Comprehensive Cancer Center (Winston-Salem, NC, USA)
- National Cancer Institute (Bethesda, MD, USA) [P30CA012197]
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Objective. The FLT3 internal tandem duplication (Flt3-ITD) confers a worse prognosis for patients with acute myeloid leukemia (AML); however, the mechanisms involved are unknown. As AML is treated with cytarabine (Ara-C) and an anthracycline, we sought to determine the effects of the Flt3-ITD on response to these agents. Materials and Methods. A genetically defined mouse model of AML was used to examine the effects of the Flt3-ITD on response to cytarabine and doxorubicin in vitro and in vivo. Results. In vitro, the Flt3-ITD conferred resistance to doxorubicin and doxorubicin plus AraC, but sensitivity to Ara-C alone. This resistance was reversible by the Flt3-ITD inhibitor sorafenib. The Flt3-ITD did not affect DNA damage levels after treatment, but was associated with increased levels of p53. The p53 response was critical to the observed changes as the Flt3-ITD had no effect on chemotherapy response in the setting of p53 null AML. In vivo, the Flt3-ITD accelerated engraftment that was partially reversible by Ara-C but not doxorubicin. Additionally, Ara-C provided a significant reduction in disease burden and a survival advantage that was not increased by the addition of doxorubicin. Doxorubicin alone led to only minimal disease reduction and no survival benefit. Conclusions. These data demonstrate that the Flt3-ITD confers sensitivity to Ara-C, but resistance to doxorubicin in a manner that depends on p53. Thus, patients with Flt3-ITD positive AML may not benefit from treatment with an anthracycline. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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