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The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. (Nat Commun, Apr 2018)

Akihiko Numata1, Hui Si Kwok1, Akira Kawasaki1, Jia Li1, Qi-Ling Zhou1, Jon Kerry2, Touati Benoukraf1,Deepak Bararia1, Feng Li1, Erica Ballabio2, Marta Tapia2, Aniruddha J. Deshpande3, Robert S. Welner4,Ruud Delwel5, Henry Yang1, Thomas A. Milne2, Reshma Taneja6; Daniel G. Tenen1,7

Author Information:
1 Cancer Science Institute of Singapore, National University of Singapore
2 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, Radcliffe Department of Medicine, University of Oxford
3 Sanford Burnham Prebys Medical Discovery Institute
4 Division of Hematology/Oncology, The University of Alabama at Birmingham, Comprehensive Cancer Center
5 Department of Hematology, Erasmus University Medical Center
6 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore
7 Harvard Stem Cell Institute, Harvard Medical School

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.

Link: https://www.nature.com/articles/s41467-018-03854-0