The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
Year: 2018
Type: article
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.
Source: Nature Communications
Institutions: National University of Singapore, Cancer Science Institute of Singapore, University of Oxford, NIHR Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, Sanford Burnham Prebys Medical Discovery Institute, University of Alabama at Birmingham, Erasmus MC, Harvard University, Harvard Stem Cell Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Duke-NUS Medical School, University of Oxford, National Research Foundation, National Research Foundation Singapore, Ministry of Education - Singapore, Medical Research Council, National Medical Research Council, Japan Society for the Promotion of Science, Cancer Science Institute of Singapore, National University of Singapore, National Heart, Lung, and Blood Institute, National Cancer Institute
Awards: Targeting circadian clock genes in leukemia treatment, G4725125279, The Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis, G6412636814, Mechanisms of regulation by RNA in acute myeloid leukemia, Functional consequences of stem and progenitor cell heterogeneity, Comprehensive Cancer Center Support Grant, Development of Novel Therapeutic Strategies in Human Leukemias
OpenAlex ID: W2805713060