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Targeting RNA polymerase II Mediator subunits in cancer therapy

View ORCID ProfileHarinder Singh
PNAS March 16, 2021 118 (11) e2100115118; https://doi.org/10.1073/pnas.2100115118
Harinder Singh
aCenter for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
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  • ORCID record for Harinder Singh
  • For correspondence: harinder@pitt.edu

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  • Mediator subunit MED1 is required for E2A-PBX1–mediated oncogenic transcription and leukemic cell growth
    - Feb 04, 2021
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Targeting Transcription Factors in Cancer

Human cancers undergo an extremely diverse range of DNA mutations and rearrangements to generate oncogenes and to inactivate tumor suppressors in the process of their malignant transformation. As a consequence, decades of research have focused on the genes and the molecular pathways as well as the mechanisms that promote the growth of specific tumor cell types. This in turn has motivated the discovery and development of precision drugs that can target tumor-specific mechanisms. Although notable successes have been achieved, particularly with the targeting of oncogenes that encode protein kinases, many known drivers of human cancers have remained hitherto “undruggable” (1). These include unmutated transcription factors (TFs) such as Myc, Myb, E2F, and nuclear factor κB or chimeric transcriptional regulators generated by chromosomal translocations and novel gene fusions such as those encoding E2A-PBX1 and E2A-HLF. The DNA-binding domains of such oncogenic TFs, which confer specificity to their genomic actions, have proven to be intractable surfaces for selective and potent small molecules that can be developed into drugs.

The Roeder laboratory, along with other groups, has been analyzing the molecular properties and functions of the E2A-PBX1 fusion protein given its import as an oncogenic driver in 5 to 7% of pediatric acute lymphoblastic leukemias (ALLs). The chimeric protein is generated by the t(1;19)(q23;p13) chromosomal translocation and contains the DNA-binding domain (homeobox) of PBX1 and the transcriptional activation domains of E2A (2). In PNAS, Li et al. (3) provide deeper molecular insight into the mechanism by which E2A-PBX1 promotes dysregulated expression of a set of target genes, including an E2F family …

↵1Email: harinder{at}pitt.edu.

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References

  1. ↵
    1. C. V. Dang,
    2. E. P. Reddy,
    3. K. M. Shokat,
    4. L. Soucek
    , Drugging the ‘undruggable’ cancer targets. Nat. Rev. Cancer 17, 502–508 (2017).
    OpenUrlCrossRefPubMed
  2. ↵
    1. J. D. Licht
    , Oncogenesis by E2A-PBX1 in ALL: RUNX and more. Blood 136, 3–4 (2020).
    OpenUrl
  3. ↵
    1. Y.-L. Li et al
    ., Mediator subunit MED1 is required for E2A-PBX1–mediated oncogenic transcription and leukemic cell growth. Proc. Natl. Acad. Sci. U.S.A., doi:10.1073/pnas.1922864118 (2021).
    OpenUrlCrossRef
  4. ↵
    1. W. C. Pi et al
    ., E2A-PBX1 functions as a coactivator for RUNX1 in acute lymphoblastic leukemia. Blood 136, 11–23 (2020).
    OpenUrl

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Targeting RNA polymerase II Mediator subunits in cancer therapy
Harinder Singh
Proceedings of the National Academy of Sciences Mar 2021, 118 (11) e2100115118; DOI: 10.1073/pnas.2100115118

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Targeting RNA polymerase II Mediator subunits in cancer therapy
Harinder Singh
Proceedings of the National Academy of Sciences Mar 2021, 118 (11) e2100115118; DOI: 10.1073/pnas.2100115118
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    • Targeting Transcription Factors in Cancer
    • E2A-PBX1 Recruitment to Target Genes
    • A Tripartite Complex of RUNX1:E2A-PBX1:Mediator
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