The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.
Akihiko NumataHui Si KwokAkira KawasakiJia LiQi-Ling ZhouJon KerryTouati BenoukrafDeepak BarariaFeng LiErica BallabioMarta TapiaAniruddha J DeshpandeRobert S WelnerRuud DelwelHenry YangThomas A MilneReshma TanejaDaniel Geoffrey TenenPublished in: Nature communications (2018)
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.
Keyphrases
- acute myeloid leukemia
- transcription factor
- atrial fibrillation
- allogeneic hematopoietic stem cell transplantation
- genome wide
- genome wide identification
- dna binding
- copy number
- gene expression
- endothelial cells
- oxidative stress
- dna damage
- cell cycle arrest
- risk assessment
- skeletal muscle
- liver failure
- endoplasmic reticulum stress
- insulin resistance
- climate change
- acute lymphoblastic leukemia
- minimally invasive
- mechanical ventilation
- adipose tissue
- hematopoietic stem cell