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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 publication

DOI

10.1038/s41467-018-03854-0

Type

Journal article

Journal

Nat Commun

Publication Date

24/04/2018

Volume

9

Keywords

Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinogenesis, Cell Transformation, Neoplastic, Female, Humans, Leukemia, Myeloid, Acute, Male, Mice, Mice, Knockout, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Transcription Factors