MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia

Dorien Pastoors; Marije Havermans; Roger Mulet‐Lazaro; Leonie Smeenk; Sophie Ottema; Claudia A. J. Erpelinck-Verschueren; Stanley van Herk; Maikel Anthonissen; Tim Grob; Shruthi Subramanian; Julie A.I. Thoms; John E. Pimanda; Bas J. Wouters; H. Berna Beverloo; Torsten Haferlach; Claudia Haferlach; Johannes A. Zuber; Eric Bindels; Ruud Delwel

doi:10.1182/blood.2025028914

Cancer BiologyBloodOct 8, 2025

Peer-reviewed journal article

MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia

Dorien Pastoors iD, Marije Havermans iD, Roger Mulet‐Lazaro iD, Leonie Smeenk iD, Sophie Ottema, Claudia A. J. Erpelinck-Verschueren iD, Stanley van Herk iD, Maikel Anthonissen, Tim Grob iD, Shruthi Subramanian iD, Julie A.I. Thoms iD, John E. Pimanda iD, Bas J. Wouters iD, H. Berna Beverloo iD, Torsten Haferlach iD, Claudia Haferlach iD, Johannes A. Zuber iD, Eric Bindels iD, Ruud Delwel iD

Abstract

Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in an aggressive subtype of acute myeloid leukemia (AML). Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of myeloid differentiation factor CEBPA. MECOM depletion is also accompanied by a severe loss of stem cells and gain of differentiation. MECOM exerts its inhibitory effect by binding to the +42kb CEBPA enhancer, a gene essential for neutrophil development. This is partially dependent on the interaction between MECOM and its co-repressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, AML patients with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA. Our study directly connects two main players of myeloid transformation MECOM and CEBPA, and it provides insight into the mechanism by which MECOM maintains the stem cell state in a unique subtype of AML by inactivating CEBPA.

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