Abstract 3906: Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC)

Abstract

Acute myeloid leukemia (AML) is a lethal blood cancer. Clinical evidence has highlighted the critical role for leukemic stem cells (LSCs) in the high relapse rate of AML patients. Understanding the signaling pathways critical for LSC function will facilitate the development of new therapies to target LSCs. G protein-coupled receptors (GPCRs) are the most successful drug targets with approximately 36% of currently marketed drugs targeting human GPCRs (Rask-Andersen et al., Nat Rev Drug Discov 2011). Aberrant expression of GPCRs has been observed in various cancers and the importance of GPCRs in cancer stem cells has begun to be appreciated. In this study, our gene expression profiling analysis identified a novel GPCR (hereafter named NG), which was suppressed in LSCs compared to normal hematopoietic stem cells. Overexpression of NG in pre-LSCs severely impaired leukemia initiation and progression in mice, whereas knockdown of NG significantly accelerated the disease onset. Our data also showed that NG overexpression substantially downregulated several well-known Wnt/β-catenin targets (e.g., Tcf7l2, c-Fos and Ccnd1). These data support a tumor suppressive role for NG in inhibiting leukemogenesis via downregulation of Wnt/β-catenin signaling. Consistent with these observations, treatment with an agonist that specifically activates the NG signaling pathway induced a marked decrease in cell viability and growth in murine LSCs and in human AML THP-1 cells, but had no effects on human AML MOLM-13 cells. This agrees with our finding that NG specifically targets the Wnt/β-catenin signaling, and the inhibitory effect of the agonist might largely depend on β-catenin expression levels in human AML cells, wherein THP-1 has been reported to express endogenous β-catenin but MOLM-13 exhibits no detectable β-catenin expression (Man CH. et al. Blood 2015). In summary, our data support a tumour suppressor role for NG in leukemogenesis and the forced expression of NG may provide a means to eradicate LSCs. Thus, restoring NG by the agonist treatment represents a promising therapeutic strategy for AML treatment. Citation Format: Florida Voli, Hangyu Yi, Estrella Gonzales-Aloy, Jenny Yingzi Wang. Targeting a novel G-protein coupled receptor (GPCR) for elimination of leukemia stem cells (LSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3906. doi:10.1158/1538-7445.AM2017-3906