Taken together, these findings highlight a previously unappreciated underlying mechanism in NOTCH1-driven T-ALL pathogenesis in which the ESCRT protein CHMP5 functions as critical positive regulator of the BRD4-p300 dependent transcription of T-ALL genes, including MYC that is essential for initiation and progression of these T-ALL disease subtype. Here, CHMP5 is linked to acute lymphoblastic leukemia.