Targeted therapy of acute myeloid leukemias (AML) is difficult due to the heterogeneity of the disease. All- trans retinoic acid (ATRA) is currently the only known therapy to work in a subset of AML. Clinicians at the University of Pennsylvania recently demonstrated that the FDA approved retinoid X receptor (RXR) agonist bexarotene stimulated leukemic cell differentiation in a subset of patients with relapsed AML leading to sustained clinical responses. The following proposal aims to characterize the mechanism by which bexarotene induces differentiation in this unique set of patients to further the understanding of how perturbations in RXR stimulated pathways result in acute myeloid leukemias. A pharmacogenetic approach to study the effects of bexarotene on AML cell lines and primary cells will be used. Using AML cell lines and primary cells that have been characterized to be unresponsive and responsive to bexarotene induced differentiation in vitro, we will first define the contribution of RXR activation and dimerization with other nuclear receptors using RNA interference of RXR in responsive AML cells and introduction of the heterodimerization mutant Y402A. Second, we will determine the effects of constitutive up or down- regulation of RXRa on lineage fate and determine the consequence of expression of the non-degradable RXRa S260A mutant on lineage fate determination after stimulation with RXR and RAR agonists. Finally, we will characterize the novel induction of the myeloid transcription factor CEBPe by bexarotene and determine if clinical responses in patients are due to restoration of expression or function of this gene. These studies will provide a more thorough understanding of the regulatory mechanisms of bexarotene-induced differentiation in vitro to further the comprehension of bexarotene responsive AML patients in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01CA129151-01A2
Application #
7741035
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$133,104
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Blobel, Gerd A; Kalota, Anna; Sanchez, Patricia V et al. (2011) Short hairpin RNA screen reveals bromodomain proteins as novel targets in acute myeloid leukemia. Cancer Cell 20:287-8
Sarry, Jean-Emmanuel; Murphy, Kathleen; Perry, Robin et al. (2011) Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rýýc-deficient mice. J Clin Invest 121:384-95
Zhao, F; Mancuso, A; Bui, T V et al. (2010) Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming. Oncogene 29:2962-72
Dierov, J; Sanchez, P V; Burke, B A et al. (2009) BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold. Leukemia 23:279-86
Sanchez, P V; Perry, R L; Sarry, J E et al. (2009) A robust xenotransplantation model for acute myeloid leukemia. Leukemia 23:2109-17