CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias
Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, but the mechanisms through which these programs are propogated remain poorly understood. The increased expression of the stem cell transcription factor, MECOM, underlies a key driver mechanism in largely incurable AMLs. However, how MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing prodifferentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kilobase (kb) downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, the targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. These findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.
Authors
- Vijay G. Sankaran (ORCID: https://orcid.org/0000-0003-0044-443X)
- Seth Goldman (ORCID: https://orcid.org/0000-0001-5096-3778)
- Jennifer A. Perry (ORCID: https://orcid.org/0000-0001-9328-1574)
- Lara Wahlster (ORCID: https://orcid.org/0000-0001-8409-7580)
- Kimberly Stegmaier (ORCID: https://orcid.org/0000-0003-0218-7895)
- Kellie R. Machlus (ORCID: https://orcid.org/0000-0002-2155-1050)
- Fiona Reed (ORCID: https://orcid.org/0000-0003-1479-7236)
- Mark D. Minden (ORCID: https://orcid.org/0000-0002-9089-8816)
- João A. Paulo (ORCID: https://orcid.org/0000-0002-4291-413X)
- Michael C. Gundry (ORCID: https://orcid.org/0000-0003-3654-1741)
- Kevin Dong (ORCID: https://orcid.org/0000-0002-2341-8472)
- Mateusz Antoszewski (ORCID: https://orcid.org/0000-0002-7651-0547)
- Claudia A. Mimoso (ORCID: https://orcid.org/0000-0001-8454-7684)
- Sander Lambo (ORCID: https://orcid.org/0000-0002-2357-3114)
- Karen Louise Adelman (ORCID: https://orcid.org/0000-0001-5364-334X)
- Volker Hovestadt (ORCID: https://orcid.org/0000-0002-3480-6649)
- Travis Fleming (ORCID: https://orcid.org/0000-0003-0993-4152)
- Yana Pikman (ORCID: https://orcid.org/0000-0002-5336-0216)
- María N. Barrachina (ORCID: https://orcid.org/0000-0002-1701-6899)
- Richard A. Voit (ORCID: https://orcid.org/0000-0002-6790-8641)
- Andrea Arruda (ORCID: https://orcid.org/0000-0003-2516-8005)
- Steven P. Gygi (ORCID: https://orcid.org/0000-0001-7626-0034)
- Sanjana Shah (ORCID: https://orcid.org/0000-0002-7389-328X)
- Riccardo Piussi
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- Dana-Farber Cancer Institute (US)
- Boston Children's Museum (US)
- Harvard Stem Cell Institute (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Blood
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1182/blood.2025028954
- Citations
- 4
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- National Science Foundation
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Dana-Farber Cancer Institute
- Edward P. Evans Foundation
- National Institutes of Health