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 theUniversity of Pennsylvania recently demonstrated that the FDA approved retinoid X receptor (RXR) agonistbexarotene stimulated leukemic cell differentiation in a subset of patients with relapsed AML leading tosustained clinical responses. The following proposal aims to characterize the mechanism by whichbexarotene induces differentiation in this unique set of patients to further the understanding of howperturbations in RXR stimulated pathways result in acute myeloid leukemias. A pharmacogenetic approachto study the effects of bexarotene on AML cell lines and primary cells will be used. Using AML cell lines andprimary cells that have been characterized to be unresponsive and responsive to bexarotene induceddifferentiation in vitro, we will first define the contribution of RXR activation and dimerization with othernuclear receptors using RNA interference of RXR in responsive AML cells and introduction of theheterodimerization 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-degradableRXRa S260A mutant on lineage fate determination after stimulation with RXR and RAR agonists. Finally, wewill characterize the novel induction of the myeloid transcription factor CEBPe by bexarotene and determineif clinical responses in patients are due to restoration of expression or function of this gene. These studieswill provide a more thorough understanding of the regulatory mechanisms of bexarotene-induceddifferentiation in vitro to further the comprehension of bexarotene responsive AML patients in vivo.
Despite advances in understanding the molecular pathogenesis of AML, therapy for relapsed diseaseremains inadequate with mortalities of 90%. Recently the FDA approved drug bexarotene was found toinduce a sustained clinical response in a subset of patients. This work will be important to identify themechanism of this response to further the understanding of how these pathways go awry in leukemic cells.
|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|