@article{9c6eaa5d066b4c4dbaec42448fa6f6f6,
title = "The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia",
abstract = "Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.",
author = "Akihiko Numata and Kwok, {Hui Si} and Akira Kawasaki and Jia Li and Zhou, {Qi Ling} and Jon Kerry and Touati Benoukraf and Deepak Bararia and Feng Li and Erica Ballabio and Marta Tapia and Deshpande, {Aniruddha J.} and Welner, {Robert S.} and Ruud Delwel and Henry Yang and Milne, {Thomas A.} and Reshma Taneja and Tenen, {Daniel G.}",
note = "Funding Information: This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education, Singapore Translational Research Award from the Singapore National Medical Research Council (NMRC/STaR/0018/2013 to DGT), National University Hospital System Aspiration Grant (NUHSRO/2014/088/AF-Partner/ 04 to RT and DGT), and Medical Research Council (MRC, UK) Molecular Haematology Unit grant (MC_UU_12009/6 to TAM, JK, MT and EB). We would like to thank M. Rossner (Ludwig Maximilian University of Munich) for providing Sharp1 knockout mice, and A. Yokoyama (NCC Tsuruoka Metabolomics Lab) for providing MLL deletion constructs. We thank C. A. Q. Chin (CSI Singapore) for proofreading of the manuscript, H.Q. Hong and G. Chong (CSI Singapore) for making MLL-AF6 construct, R. Thorne (Oxford University) for ChIP-seq data transfer, and members of the Tenen laboratory and CSI Singapore for many helpful discussions. We thank CSI Singapore FACS facility and Duke-NUS Genome Biology Facility for technical support. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-03854-0",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}