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)
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: | https://repository.cshl.edu/id/eprint/30994 |
Actions (login required)
 |
Administrator's edit/view item |