6mak

HBO1 is required for the maintenance of leukaemia stem cells

spinqualitylabelsall models 6mak, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6mak is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACO, ZN NonStd Res: ALY Gene: KAT7, HBO1, HBOa, MYST2 (HUMAN), BRD1 (HUMAN) Activity: Histone acetyltransferase, with EC number 2.3.1.48 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KAT7_HUMAN] Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Through chromatin acetylation it may regulate DNA replication and act as a coactivator of TP53-dependent transcription. Acts as a coactivator of the licensing factor CDT1 (PubMed:18832067). Specifically represses AR-mediated transcription. Publication Abstract from PubMed Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings. HBO1 is required for the maintenance of leukaemia stem cells.,MacPherson L, Anokye J, Yeung MM, Lam EYN, Chan YC, Weng CF, Yeh P, Knezevic K, Butler MS, Hoegl A, Chan KL, Burr ML, Gearing LJ, Willson T, Liu J, Choi J, Yang Y, Bilardi RA, Falk H, Nguyen N, Stupple PA, Peat TS, Zhang M, de Silva M, Carrasco-Pozo C, Avery VM, Khoo PS, Dolezal O, Dennis ML, Nuttall S, Surjadi R, Newman J, Ren B, Leaver DJ, Sun Y, Baell JB, Dovey O, Vassiliou GS, Grebien F, Dawson SJ, Street IP, Monahan BJ, Burns CJ, Choudhary C, Blewitt ME, Voss AK, Thomas T, Dawson MA Nature. 2019 Dec 11. pii: 10.1038/s41586-019-1835-6. doi:, 10.1038/s41586-019-1835-6. PMID:31827282 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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