Revisiting the therapeutic potential of fenretinide in acute erythroid and acute megakaryoblastic leukemias

Abstract N-(4-hydroxyphenyl)retinamide (4-HPR, also known as Fenretinide) is a synthetic derivative of vitamin A with well-established anti-cancer properties. These properties include the rapid generation of reactive oxygen species, induction of stress responses and apoptosis, and repression of NF-κB and Wnt signaling pathways. Here, we report the transcription factor GATA1 as a novel target of Fenretinide, positioning Fenretinide as a promising therapeutic candidate for two aggressive subtypes of acute myeloid leukemia (AML): acute erythroleukemia (M6) and acute megakaryocytic leukemia (M7). These subtypes of AML have the poorest prognosis, with a median survival of only a few months despite active treatment. Using data from the Cancer Cell Line Encyclopedia and CRISPR screening from DepMap, we found that M6 and M7 AMLs exhibit high expression of GATA1 and are dependent on it for survival. GATA1 has been implicated in promoting AML cell proliferation and conferring resistance to chemotherapy. Despite its importance, GATA1 has long been considered “undruggable.” Here, we demonstrate that Fenretinide inhibits GATA1 expression in both M6/M7 AML cell lines and primary M6/M7 patient samples at concentrations as low as 0.35-2 µM, concentrations readily achievable in vivo with Fenretinide. GATA1 knockdown induces cytotoxicity comparable to low-dose Fenretinide treatment, while GATA1 overexpression rescues cells from low-dose Fenretinide-induced cytotoxicity. Furthermore, Fenretinide sensitizes M6/M7 AML cells to standard-of-care (SOC) therapies, particularly the Bcl-2 inhibitor venetoclax. Mechanistically, combination treatment with 4-HPR and SOC therapies leads to downregulation of BCL-XL, an anti-apoptotic protein known to contribute to M6/M7 resistance to Bcl-2 inhibitors. Interestingly, gene expression analysis following GATA1 knockdown reveals modulation of genes involved in immune-related pathways. Given the availability of clinical formulations, well documented clinical tolerability, and the lack of effective therapeutic options for M6/M7 AML, we propose that the therapeutic potential of Fenretinide warrants further exploration in patients with these aggressive subtypes of AML.