Abstract 1501: Developing novel strategy for the treatment of acute myeloid leukemia by targeting retinoic acid signaling pathways

Abstract

Abstract Retinoic acid (RA), the active metabolite of vitamin A, influences biological processes by activating the retinoic acid receptor (RAR). RARs are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. The success of RAR modulation in the treatment of acute promyelocytic leukaemia (APL) particularly by the use of all-trans retinoic acid (atRA) has stimulated considerable interest in the development of small molecules that can modulate RAR and RXR. Recent studies have demonstrated that RA can also activate the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). In the aqueous intracellular milieu, RA is transported by the cellular retinoid-binding protein CRABP-II, or by the fatty-acid-binding protein FABP5, depending on the ratio of FABP5 to CRABP-II. In cells expressing high CRABP-II and low FABP5, RA activates the RAR, whereas in the presence of the reverse ratio, RA activates PPAR β/δ. These two different mode of RA delivery due to different ratio of these two cargos leads to opposite cellular outcomes. Cells harboring high level of CRABP-II, RA is delivered to RAR leading to apoptosis, growth arrest, and anticancer activity. However, when FABP5 expression is high RA is delivered to PPAR β/δ resulting in survival, proliferation, and tumor growth. In both cases, retinoid X receptor (RXR) is the indispensable partner of the nuclear receptor involved. The analysis of TCGA data set revealed that a certain class of AML patients have low level of CRABP-II and high level of FABP5, that in part explain the inability of at-RA to induce terminal differentiation in AML cells. To test our hypothesis, we screened AML and APL patient bone marrow cells and found that a number of AML patients bone marrow have high FABP5 and low CRABP-II protein levels while the atRA responding APL patients has opposite ratio determined by western blotting. Therefore, low CRABP-II and high FABP5 levels in a subset of AML patients lead to the activation of pro-survival PPAR β/δ pathway that promotes proliferation and opposes the differentiation. We also analyzed different AML cell lines for mRNA expression using qRT-PCR and protein by western blotting in using highly specific antibodies against FABP5 and CRABP-II. High FABP5 levels were observed in the majority of the AML cell lines. Efficacy of novel small molecule FABP5 inhibitor as a single agent and in combination with atRA was evaluated in HL-60 cells. Here, we demonstrate that a small molecule inhibitor of FABP5 synergizes with atRA and induces the differentiation in AML cells. Citation Format: Metis Hasipek, Dale Grabowski, James G. Phillips, Yihong Guan, Hetty Carraway, Jaroslaw Maciejewski, Babal K. Jha. Developing novel strategy for the treatment of acute myeloid leukemia by targeting retinoic acid signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1501.