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; Daniel G. Tenen

doi:10.1038/s41467-018-03854-0

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, Daniel G. Tenen

Hematology/Oncology/Cardiovascular

Research output: Contribution to journal › Article

3 Citations (Scopus)

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.

Original language	English
Article number	1622
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03854-0
Publication status	Published - Dec 1 2018

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All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Cite this

Numata, A., Kwok, H. S., Kawasaki, A., Li, J., Zhou, Q. L., Kerry, J., ... Tenen, D. G. (2018). The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nature communications, 9(1), [1622]. https://doi.org/10.1038/s41467-018-03854-0

The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. / Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira; Li, Jia; Zhou, Qi Ling; Kerry, Jon; Benoukraf, Touati; Bararia, Deepak; Li, Feng; Ballabio, Erica; Tapia, Marta; Deshpande, Aniruddha J.; Welner, Robert S.; Delwel, Ruud; Yang, Henry; Milne, Thomas A.; Taneja, Reshma; Tenen, Daniel G.

In: Nature communications, Vol. 9, No. 1, 1622, 01.12.2018.

Research output: Contribution to journal › Article

Numata, A, Kwok, HS, Kawasaki, A, Li, J, Zhou, QL, Kerry, J, Benoukraf, T, Bararia, D, Li, F, Ballabio, E, Tapia, M, Deshpande, AJ, Welner, RS, Delwel, R, Yang, H, Milne, TA, Taneja, R & Tenen, DG 2018, 'The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia', Nature communications, vol. 9, no. 1, 1622. https://doi.org/10.1038/s41467-018-03854-0

Numata, Akihiko ; Kwok, Hui Si ; Kawasaki, Akira ; Li, Jia ; Zhou, Qi Ling ; Kerry, Jon ; Benoukraf, Touati ; Bararia, Deepak ; Li, Feng ; Ballabio, Erica ; Tapia, Marta ; Deshpande, Aniruddha J. ; Welner, Robert S. ; Delwel, Ruud ; Yang, Henry ; Milne, Thomas A. ; Taneja, Reshma ; Tenen, Daniel G. / The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. In: Nature communications. 2018 ; Vol. 9, No. 1.

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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.",

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