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January 22nd, 2025
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Stony Brook University
cancer biology
biorxiv

Fenretinide targets GATA1 to induce cytotoxicity in GATA1 positive Acute Erythroid and Acute Megakaryoblastic Leukemic cells.

Raza, Y.Open in Google Scholar•Yu, G.Open in Google Scholar•Chiappone, S. B.Open in Google Scholar•Liu, S.Open in Google Scholar•Luberto, C.Open in Google Scholar

Patients with Acute Myeloid Leukemia (AML) subtypes, acute erythroleukemia and acute megakaryocytic leukemia (M6 and M7 AMLs, respectively) have a median survival of only a few months with no targeted effective treatment. Our gene expression analysis using the Cancer Cell Line Encyclopedia and CRISPR screen from DepMap showed that M6/M7 AMLs have high levels of the transcription factor GATA1 and depend on GATA1 for survival. While GATA1 was shown to support AML cell proliferation and resistance to chemotherapy, GATA1 has long been considered undruggable. Here, we identify the small molecule N-(4-hydroxyphenyl)retinamide (4-HPR, Fenretinide) as a novel GATA1 targeting agent in M6 and M7 AML cells, with nM to low uM concentrations of 4-HPR causing loss of GATA1. In M6 AML OCIM1 cells, knock-down of GATA1 induced cytotoxicity similarly to low doses 4-HPR while overexpression of GATA1 significantly protected cells from 4-HPR-induced cytotoxicity. In M6 AML cells, 4-HPR synergized with the current standard-of-care (SOC), Azacytidine plus Venetoclax, overcoming cell resistance to the drugs. As single-agent, 4-HPR outperformed SOC. 4-HPR is a synthetic derivative of vitamin A, and numerous clinical trials have supported its safe profile in cancer patients; therefore, targeted use of 4-HPR against M6 and M7 AMLs may represent a novel therapeutic breakthrough.

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