MECOM is a master repressor of myeloid differentiation through dose control of <i>CEBPA</i> in acute myeloid leukemia
Abstract
Abstract The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
Article Details
Authors (19)
Dorien Pastoors
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Marije Havermans
Roger Mulet-Lazaro
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Leonie Smeenk
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Sophie Ottema
3Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands
Claudia Erpelinck-Verschueren
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Stanley van Herk
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Maikel Anthonissen
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Tim Grob
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Shruthi Subramanian
4School of Clinical Medicine, University of New South Wales, Sydney, Australia
Julie A. I. Thoms
John E. Pimanda
Bas J. Wouters
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Berna Beverloo
3Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Claudia Haferlach
8Munich Leukemia Laboratory, Munich, Germany
Johannes Zuber
Eric Bindels
Department of Hematology, Erasmus MC University Medical Center
Ruud Delwel