{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:53:43Z","timestamp":1768510423817,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,31]]},"group-title":"Cancer Biology","reference-count":100,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,31]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Oncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notably\n                  <jats:italic>MYC<\/jats:italic>\n                  . Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"577409v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Identification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcription<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>CHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genes<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>P300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        CHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiation\n                        <jats:italic>in vivo<\/jats:italic>\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.29.577409","type":"posted-content","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T20:40:30Z","timestamp":1706733630000},"source":"Crossref","is-referenced-by-count":0,"title":["The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent 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