The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia

Akihiko Numata, Hui Si Kwok, Akira Kawasaki, Jia Li, Qi-Ling Zhou, Jon Kerry, Touati Benoukraf, Deepak Bararia, Feng Li, Erica Ballabio, Marta Tapia, Aniruddha J. Deshpande, Robert S. Welner, Ruud Delwel, Henry Yang, Thomas A. Milne, Reshma Taneja () and Daniel G. Tenen ()
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Akihiko Numata: National University of Singapore
Hui Si Kwok: National University of Singapore
Akira Kawasaki: National University of Singapore
Jia Li: National University of Singapore
Qi-Ling Zhou: National University of Singapore
Jon Kerry: University of Oxford
Touati Benoukraf: National University of Singapore
Deepak Bararia: National University of Singapore
Feng Li: National University of Singapore
Erica Ballabio: University of Oxford
Marta Tapia: University of Oxford
Aniruddha J. Deshpande: Sanford Burnham Prebys Medical Discovery Institute
Robert S. Welner: Comprehensive Cancer Center
Ruud Delwel: Erasmus University Medical Center
Henry Yang: National University of Singapore
Thomas A. Milne: University of Oxford
Reshma Taneja: National University of Singapore
Daniel G. Tenen: National University of Singapore

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03854-0

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