CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias
Abstract
Abstract 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.
Article Details
Authors (24)
Travis J. Fleming
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Mateusz Antoszewski
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Sander Lambo
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Michael C. Gundry
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Riccardo Piussi
1San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
Lara Wahlster
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Sanjana Shah
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Fiona E. Reed
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Kevin D. Dong
5Department of Cell Biology, Harvard Medical School, Boston, MA
Joao A. Paulo
Steven P. Gygi
Claudia Mimoso
6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
Seth R. Goldman
6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
Karen Adelman
Ludwig Center at Harvard, Harvard Medical School
Jennifer A. Perry
Yana Pikman
Kimberly Stegmaier
Department of Pediatric Oncology, Dana-Farber Cancer Institute
Maria N. Barrachina
7Vascular Biology Program, Boston Children’s Hospital, Boston, MA
Kellie R. Machlus
7Vascular Biology Program, Boston Children’s Hospital, Boston, MA
Volker Hovestadt
Andrea Arruda
Princess Margaret Cancer Centre, University Health Network
Mark D. Minden
Princess Margaret Cancer Centre, University Health Network
Richard A. Voit
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
Vijay G. Sankaran