Together, our findings highlight a fundamental mechanism of T-ALL pathogenesis in which the ESCRT protein CHMP5 functions as a positive regulator of the BRD4-p300 dependent transcription of T-ALL genes, including MYC, a key transcription factor that enables T-ALL initiation and maintenance of NOTCH1-driven T-ALL. This evidence concerns the gene EP300 and acute lymphoblastic leukemia.