BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

Acute myeloid leukemia (AML) cells treated with bromodomain and extraterminal domain (BET) inhibitors show defects in oxygen consumption rates (OCRs) and extracellular acidification. The decreased OCR and extracellular acidification rate (ECAR) indicate repression of both mitochondrial dynamics and glycolytic function. AbstractInhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0/G1 arrest, and with time, cause cell death. Meta ‐analysis of PRO‐seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addi tion, gene expression analysis showed that transcription ofBCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 ...
Source: Journal of Cellular Biochemistry - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research