Abstract 5334: Proliferative signaling through the ras-erk pathway can be inhibited by the overexpression of dual-specific phosphatase genes in collaboration with other negative regulators of cell cycle progression in the acute myeloid cell line HL-6

Abstract Reversing or reprogramming malignant cells toward their normal gene expression patterns, without repairing their oncogenic mutations, can be accomplished in culture as demonstrated by the treatment of certain acute myeloid leukemia (AML) cell lines with phorbol esters, which through the activation of PKC results in cell cycle arrest, myeloid differentiation, and ultimately programmed cell death. Gene therapy continues to show promise in the development of new and effective cancer treatments. At its inception, replacing deficient tumor suppressor gene functions was an attractive goal and with the development of gene editing strategies, the repair of activated oncogenes is possible. Here we report the delivery and overexpression of negative regulators of oncogenic RAS signaling, through transfection, that provide tumor suppressor functions in the NRAS-driven cell line, HL-60, that inhibit their proliferative competency. Genes belonging to the dual-specific phosphatase family (DUSPs), including DUSP1, 5 and 6, along with RAS-ERK pathway inhibitors RASA1 and SPRY2, when transfected and overexpressed in HL-60 cells, affects decreases in phospho-ERK and Ki67 levels resulting in reduced proliferation. In combination with the overexpression of genes encoding the cyclin-CDK inhibitors, CDKN1A and CDKN2B, these anti-proliferative alterations are enhanced. While efficient strategies wait for the delivery of lacking tumor suppressor functions to cancer cells through targeted gene therapies, we propose candidate genes for reversing the proliferation program of RAS-driven AML cells. Citation Format: Michael Roberts, Amelia Harper, Kishan Mangru, Katy Meta, Sophia Kovatsis, Jeffrey Forrester, Grace Crossland, Cuong Nguyen, Sher Bahadur. Proliferative signaling through the ras-erk pathway can be inhibited by the overexpression of dual-specific phosphatase genes in collaboration with other negative regulators of cell cycle progression in the acute myeloid cell line HL-60 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5334.