The Basic Helix-loop-helix Transcription Factor SHARP1 is an Oncogenic Driver in MLL-AF6 Acute Myelogenous Leukemia

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Apr 26

PMID 29692408

Citations 12

Authors

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

Affiliations

Soon will be listed here.

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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