CHMP5-Mediated Transcriptional Regulation of T-Cell Acute Lymphoblastic Leukemia (CHIPseq)
Oncogene activity rewires cellular transcription to create new transcriptional networks which cancer cells become addicted to through mechanisms that remain unresolved. Using human and mouse models of T-cell acute lymphoblastic leukemia (T-ALL), we identified an essential requirement of the endosomal sorting complex required for transport (ESCRT) protein CHMP5 in enabling the T-ALL transcriptional program. Loss of CHMP5 impaired recruitment of the bromodomain transcriptional coactivator BRD4 to enhancer and super-enhancers which caused RNA polymerase II stalling, resulting in severe downregulation of key pro-leukemogenic genes, including MYC and MYC-target genes. Mechanistically, CHMP5 facilitated BRD4 interaction with the histone acetyl transferase p300 to promote H3K27 acetylation at pro-T-ALL gene regulatory elements. Validating its importance to T-cell leukemogenesis, CHMP5-deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL initiation by oncogenic NOTCH1 in vivo. Collectively, our results uncover an unexpected transcriptional activity of CHMP5 that is essential for T-ALL pathogenesis. Overall design: CHIPseq of BRD4, Pol II, and H3K27ac from CUTLL1 cells treated with control shRNA (CT) and CHMP5 shRNA (KD).