(E,E)-bisantrene suppresses MYC expression and displays anti-leukemic activity in acute myeloid leukemia

Acute myeloid leukemia (AML) presents a significant challenge due to its genetic variability and therapeutic resistance. The transcription factor MYC is a key contributor to AML progression. (E,E)-bisantrene has recently shown the ability to inhibit MYC transcription and its downstream effects through stabilizing G-quadruplex DNA.

This study aimed to investigate the mechanism of action and preclinical efficacy of (E,E)-bisantrene in various AML models, including cell lines, xenograft mouse models, and ex vivo human AML mononuclear cells. The effects of (E,E)-bisantrene were assessed by examining transcriptomic, proteomic, and phosphoproteomic changes after treatment.

The research revealed potent anti-proliferative activity of (E,E)-bisantrene across multiple AML cell lines, causing apoptosis and reducing the S phase proportion. The prolonged survival in cell and patient-derived xenograft models further supports its potential. Mechanistically, RNA-seq and proteomic analyses demonstrated significant reductions in MYC and E2F activity, as well as cell cycle regulators CDK1/2/4/5 following (E,E)-bisantrene treatment.

There was also a dose- and time-dependent decrease in MYC levels, alongside alterations in TP53 and inflammation-associated transcript signatures. These findings suggest that the anti-proliferative effect of (E,E)-bisantrene in preclinical AML models is linked to the downregulation of MYC, CDK1/2/4/5, and E2F. The results support the ongoing clinical evaluation of (E,E)-bisantrene for AML, particularly in cases where MYC is a clinically relevant driver of disease aggressiveness and therapy resistance.