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Ref Type Journal Article
PMID (27294782)
Authors Gilan O, Lam EY, Becher I, Lugo D, Cannizzaro E, Joberty G, Ward A, Wiese M, Fong CY, Ftouni S, Tyler D, Stanley K, MacPherson L, Weng CF, Chan YC, Ghisi M, Smil D, Carpenter C, Brown P, Garton N, Blewitt ME, Bannister AJ, Kouzarides T, Huntly BJ, Johnstone RW, Drewes G, Dawson SJ, Arrowsmith CH, Grandi P, Prinjha RK, Dawson MA
Title Functional interdependence of BRD4 and DOT1L in MLL leukemia.
Journal Vol Issue Date Pages Journal Short Title
Nature structural & molecular biology 23 7 2016 Jul 673-81 Nat Struct Mol Biol
URL
Abstract Text Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A fusion acute myeloid leukemia sensitive I-BET151 + SGC0946 Preclinical - Patient cell culture Actionable In a preclinical study, I-BET151 and SGC0946 synergistically inhibited proliferation of patient-derived acute myeloid leukemia cells harboring KMT2A fusions in culture (PMID: 27294782). 27294782