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.

Public Health Relevance

Despite advances in understanding the molecular pathogenesis of AML, therapy for relapsed disease remains inadequate with mortalities of 90%. Recently the FDA approved drug bexarotene was found to induce a sustained clinical response in a subset of patients. This work will be important to identify the mechanism of this response to further the understanding of how these pathways go awry in leukemic cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA129151-05
Application #
8474703
Study Section
Subcommittee G - Education (NCI)
Program Officer
Vallejo-Estrada, Yolanda
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$143,425
Indirect Cost
$10,624
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sanchez, P V; Glantz, S T; Scotland, S et al. (2014) Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors. Leukemia 28:749-60
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