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The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
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The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
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Journal Article
The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
2018
Overview
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.
Gene fusions involving MLL and different partner genes define unique subgroups of acute myelogenous leukemia, but the mechanisms underlying specific subgroups are not fully clear. Here the authors elucidate the mechanisms of MLL-AF6 induced transformation, providing a distinct pathway that involves SHARP1 as a critical target.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/31
/ 13/89
/ 38/15
/ 38/22
/ 38/39
/ 38/43
/ 38/77
/ 38/90
/ 64/60
/ 82/80
/ Animals
/ Basic Helix-Loop-Helix Transcription Factors - genetics
/ Basic Helix-Loop-Helix Transcription Factors - metabolism
/ Cell Transformation, Neoplastic
/ Female
/ Genomes
/ Helix-loop-helix proteins (basic)
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - metabolism
/ Leukemia, Myeloid, Acute - pathology
/ Male
/ Mice
/ Myeloid-Lymphoid Leukemia Protein - genetics
/ Myeloid-Lymphoid Leukemia Protein - metabolism
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Proteins
/ Science
