Abstract 1674: Inhibition of oncogenic nras signaling in acute myeloid leukemia cell lines through directed transcriptome alterations

Abstract

Abstract Oncogenic mutations in genes involved in proliferative signaling are hallmarks of malignant transformation. The Ras family of signal transducing proteins are involved in the activation of several proliferative pathways and therefore are found to be oncogenically mutated in a variety of cancer types. The NRAS-directed pathways resulting in Erk1/2 activation are dysregulated in a significant percentage of acute myeloid leukemia (AML), metastatic melanoma, Hodgkin lymphoma, and thyroid cancers. The consequence of oncogenic NRAS signaling is the establishment of a transcriptome commanding constitutive proliferation and survival. It has long been known that phorbol ester treatment of AML cell lines, resulting in activation of protein kinase C (PKC), causes phenotypic changes that include cell cycle arrest, myeloid differentiation, and apoptosis. The paradox is that numerous studies identify PKC as an activator of RAS/ERK signaling. Here we show that phorbol ester treatment of NRAS-driven AML cell lines results in the transcriptional upregulation of genes encoding negative regulators of RAS signaling including DUSP1,2,4,5,6, SPRY2, SPRED1, RASA1, PEA15, RPS6KA1, and RASSF5. Additionally, phorbol ester treatment eventually results to ERK1/2 inactivation through dephosphorylation. Several of these negative regulators, when overexpressed in AML cell lines, dampen proliferation, and induce senescence. We propose that the induction of RAS negative regulators alters the AML transcriptome to a non-proliferative state in part through the transcriptional regulation of genes such as CDKN1A, CDKN2B, ZFP36L1, and MYC. As gene therapy strategies develop, designed to provide negative regulators of proliferative signaling pathways that are repressed in the malignant cell, we imagine the RAS/ERK pathway as a target for transcriptome reprogramming. Citation Format: Michael Roberts, Sophia Kovatsis, Amelia Harper, Megan Cravinho, Kishan Mangru, Sher Bahadur, Keagan Hesse, Katy Meta, Cuong Nguyen. Inhibition of oncogenic nras signaling in acute myeloid leukemia cell lines through directed transcriptome alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1674.