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
Li, Jia
Kerry, Jon
Ballabio, Erica
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Abstract
© 2018 The Author(s). 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.
Keywords
Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, ACUTE MYELOID-LEUKEMIA, MIXED-LINEAGE LEUKEMIA, STEM-CELLS, HISTONE METHYLTRANSFERASE, ACTIVE ENHANCERS, BINDING PROTEIN, GENE-EXPRESSION, TARGET GENES, DNA-DAMAGE, MLL
Source Title
NATURE COMMUNICATIONS
Publisher
NATURE PUBLISHING GROUP
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Date
2018-04-24
DOI
10.1038/s41467-018-03854-0
Type
Article