Pardee, T. S., Zuber, J., Lowe, S. W. (May 2009) Effects of the Flt3 ITD on response to chemotherapy in a murine model of acute myeloid leukemia. Journal of Clinical Oncology, 27 (15). p. 7060. ISSN 0732-183X
Abstract
Background: Acute myeloid leukemia (AML) is an aggressive, genetically heterogeneous malignancy. This heterogeneity is thought to underlie the divergent responses to treatment observed and contribute to relapse. The Flt3 receptor tyrosine kinase containing an internal tandem duplication (Flt3 ITD) is a common mutation in AML and associated with a poor prognosis; however, its effect on chemotherapy response is currently unknown. Methods: Murine AML was generated by retroviral transduction of an MLL-ENL fusion protein into fetal liver cells and subsequent transplantation into syngeneic mice. Blasts were harvested from moribund animals and myeloid lineage confirmed by immunophenotyping. Flt3 ITD sequence was inserted into a GFP tagged vector. Blasts were infected with Flt3 ITD or control virus. For competition assays mixtures of infected and uninfected blasts were exposed to chemotherapy for 72 hours. Among the remaining viable cells, percentages of infected blasts were determined by flow cytometry. For in vivo competition assays animals were injected with mixtures of blasts, treated with chemotherapy and percentages of Flt3 ITD positive blasts as well as total leukemic burden in femoral bone marrow was assessed. Results: Presence of the Flt3 ITD confers an advantage to doxorubicin (dox) in vitro. After exposure to dox at 5ng/mL more infected blasts remained viable when compared to controls (p = 0.0001). Presence of the Flt3 ITD increased sensitivity to cytarabine (Ara-C). After exposure to 50 nM Ara-C fewer Flt3 ITD blasts remained viable (p = 0.0293). Flt3 ITD confers sensitivity to Ara-C in vivo. Bl6 mice were injected with 1x106 blasts, 10% containing Flt3 ITD. After 12 days mice were treated for 5 days with either Ara-C at 200mg/kg, dox at 3mg/kg or observation. Ara-C treated animals had fewer Flt3 ITD blasts than controls (p = 0.0030) or dox treated animals (p < 0.0001) and lower leukemic burden (p < 0.0001). In contrast there was no difference in leukemic burden between Ara-C treated, dox treated or control animals in AML without Flt3 ITD (p = 0.2833). Conclusions: The Flt3 ITD confers resistance to doxorubicin in vitro and sensitivity to Ara-C in vitro and in vivo. These results suggest AML patients with Flt3 ITD may benefit more from high-dose cytarabine regimens then anthracyclines.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | diseases & disorders > cancer diseases & disorders organism description > animal diseases & disorders > cancer > drugs and therapies > chemotherapy diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > leukemia Publication Type > Meeting Abstract organism description > animal > mammal > rodent > mouse diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Depositing User: | Matt Covey |
| Date: | 20 May 2009 |
| Date Deposited: | 21 Feb 2013 17:54 |
| Last Modified: | 13 Mar 2018 19:09 |
| URI: | https://repository.cshl.edu/id/eprint/27366 |
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