Elucidating the importance and regulation of key enhancers for human MEIS1 expression.

Autor: Xiang P; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Yang X; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Escano L; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Dhillon I; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Schneider E; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Clemans-Gibbon J; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Wei W; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Wong J; Department of Medical Genetics, University of British Columbia, Vancouver, Canada., Wang SX; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Tam D; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada., Deng Y; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Yung E; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada., Morin GB; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada., Hoodless PA; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, Canada., Hirst M; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada., Karsan A; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Kuchenbauer F; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada.; Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, BC Cancer, Vancouver, Canada.; Department of Medicine, University of British Columbia, Vancouver, Canada., Humphries RK; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada., Rouhi A; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada. arouhi@bccrc.ca.; Department of Medicine, University of British Columbia, Vancouver, Canada. arouhi@bccrc.ca.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Aug; Vol. 36 (8), pp. 1980-1989. Date of Electronic Publication: 2022 May 27.
DOI: 10.1038/s41375-022-01602-4
Abstrakt: Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.
(© 2022. The Author(s).)
Databáze: MEDLINE
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