Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner

Pardee, T. S., Zuber, J., Lowe, S. W. (April 2011) Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner. Exp Hematol, 39 (4). 473-485 e4. ISSN 1873-2399 (Electronic)0301-472X (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21288478
DOI: 10.1016/j.exphem.2011.01.009

Abstract

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 Ara-C, 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.

Item Type: Paper
Uncontrolled Keywords: Acute Disease Animals Antineoplastic Combined Chemotherapy Protocols/therapeutic use Benzenesulfonates/administration & dosage Blotting, Western Cytarabine/administration & dosage DNA Damage Disease Models, Animal Doxorubicin/administration & dosage Drug Resistance, Neoplasm/drug effects/genetics Gene Duplication Humans Leukemia, Myeloid/drug therapy/*genetics Mice Mice, Inbred C57BL Mice, Transgenic Myeloid-Lymphoid Leukemia Protein/genetics Pyridines/administration & dosage RNA Interference Reverse Transcriptase Polymerase Chain Reaction Survival Analysis *Tandem Repeat Sequences Tumor Suppressor Protein p53/*genetics/metabolism fms-Like Tyrosine Kinase 3/*genetics
Subjects: diseases & disorders > cancer > drugs and therapies > chemotherapy
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL labs > Lowe lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: April 2011
Date Deposited: 26 Dec 2014 19:56
Last Modified: 14 Oct 2015 19:44
PMCID: PMC3062750
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30994

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