Mediator subunit MED1 is required for E2A-PBX1–mediated oncogenic transcription and leukemic cell growth
- 4 February 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (6)
- https://doi.org/10.1073/pnas.1922864118
Abstract
The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1–dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1–driven leukemia. The MED1 dependency for E2A-PBX1–mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia.Funding Information
- HHS | NIH | National Cancer Institute (CA178765)
- HHS | NIH | National Cancer Institute (CA163086)
- Ministry of Science and Technology, Taiwan (107-2320-B-010-024-MY3)
- Ministry of Science and Technology, Taiwan (104-2917-I-564-005)
- HHS | NIH | National Center for Advancing Translational Sciences (UL1TR001866)
This publication has 48 references indexed in Scilit:
- Transcription factor RUNX1 promotes survival of acute myeloid leukemia cellsJCI Insight, 2013
- Mediator-dependent nuclear receptor functionSeminars in Cell & Developmental Biology, 2011
- Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growthThe EMBO Journal, 2011
- Cyclin D3 Is Selectively Required for Proliferative Expansion of Germinal Center B CellsMolecular and Cellular Biology, 2011
- Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulationNature Immunology, 2008
- New therapeutic strategies for the treatment of acute lymphoblastic leukaemiaNature Reviews Drug Discovery, 2007
- B-cell development fails in the absence of the Pbx1 proto-oncogeneBlood, 2007
- The mediator complex functions as a coactivator for GATA-1 in erythropoiesis via subunit Med1/TRAP220Proceedings of the National Academy of Sciences of the United States of America, 2006
- E Protein Silencing by the Leukemogenic AML1-ETO Fusion ProteinScience, 2004
- Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesisNature, 2002