Abstract 2696: PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia
Authors: Sophia Hu, David Wald, Reshmi Parameswaran
Journal: Cancer Research (2014)

Abstract Acute myeloid leukemia (AML) is characterized by the differentiation arrest and rapid proliferation of abnormal white blood cells. Current therapeutics involves the use of chemotherapeutic agents, which possess high toxicities and poor efficacies. Thus, there is an unparalleled need to identify low-toxicity therapies to improve the mortality of these patients. Facilitating the maturation of acute myeloid leukemia cells induces their growth arrest and death without the need for high doses of overt toxicity from chemotherapies. Therefore, we seek to identify differentiating agents capable of inducing monocytic differentiation without deleterious side-effects on normal hematopoietic tissues. One possible approach to promote AML cellular differentiation is manipulating the activity or expression of proteins, such as PPAR delta, that are known to modulate cellular growth processes. PPAR delta is part of a family of nuclear hormone receptors that function as transcription factors to induce the activation of genes related to cellular growth, development, and metabolism. PPAR alpha and PPAR gamma have been extensively characterized in the context of leukemia. However, little is known about PPAR delta. In the current study, we sought to delineate the role of PPAR delta in AML and analyze whether inhibiting the PPAR delta pathway would induce differentiation in AML cells. Inhibiting PPAR delta led to a significant increase in monocytic differentiation in AML cell lines in vitro, as measured by immunophenotyping by flow cytometry and NBT reduction assays. For instance, we observed 3% CD11b expression in untreated HL60, OCI, NB4, and U937 cell lines and 40% CD11b expression after PPAR inhibition. Importantly, PPAR delta does not lead to toxic effects on non-leukemic cells at similar doses. These results were further supported by morphological evidence of monocytic differentiation seen from Wright-Giemsa staining and a 40% decrease in AML cell proliferation following PPAR delta inhibition using the MTT cell proliferation assay. A 34% decrease in self-renewal capabilities of leukemic cells after PPAR delta inhibition suggests permanent effects on differentiation and growth arrest, as determined by colony assays. Consistent with growth inhibition, treatment with PPAR delta inhibitors induced the expression of cell cycle and proliferation-related genes such c-Myc, p21, and p27 in a dose-dependent manner. Overall, our findings suggest that PPAR delta inhibitors may possess promising clinical relevance as potential candidates for non-toxic alternatives to chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Sophia Hu, David Wald, Reshmi Parameswaran. PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2696. doi:10.1158/1538-7445.AM2014-2696