Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 6, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1922864118
Keywords
Mediator; E2A-PBX1; leukemia; MED1; RUNX1; EBF1
Categories
Funding
- National Cancer Institute [CA178765]
- Leukemia and Lymphoma Society [SCOR 7021-20]
- Ministry of Science and Technology in Taiwan [MOST 107-2320-B-010-024-MY3, MOST 104-2917-I-564-005]
- Cancer Progression Research Center, National Yang-Ming University from the Featured Areas Research Center Program within the Ministry of Education in Taiwan
- National Center for Advancing Translational Sciences (National Institutes of Health Clinical and Translational Science Award) [UL1TR001866]
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The study reveals that the Mediator complex directly interacts with E2A-PBX1 through the MED1 subunit, playing a critical role in regulating E2A-PBX1-dependent gene activation and leukemic cell growth. The findings highlight the functional importance of MED1 in gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia, suggesting potential therapeutic opportunities by targeting MED1 in E2A-PBX1(+) pre-B leukemia.
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.
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