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CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network

Author

Listed:
  • Elizabeth A. R. Garfinkle

    (Stanford University School of Medicine)

  • Pratima Nallagatla

    (Stanford University School of Medicine)

  • Binay Sahoo

    (Stanford University School of Medicine)

  • Jinjun Dang

    (Stanford University School of Medicine)

  • Mohammad Balood

    (Stanford University School of Medicine)

  • Anitria Cotton

    (St. Jude Children’s Research Hospital)

  • Camryn Franke

    (Stanford University School of Medicine)

  • Sharnise Mitchell

    (St. Jude Children’s Research Hospital)

  • Taylor Wilson

    (St. Jude Children’s Research Hospital)

  • Tanja A. Gruber

    (Stanford University School of Medicine)

Abstract

CBFA2T3-GLIS2 is a fusion oncogene found in pediatric acute megakaryoblastic leukemia that is associated with a poor prognosis. We establish a model of CBFA2T3-GLIS2 driven acute megakaryoblastic leukemia that allows the distinction of fusion specific changes from those that reflect the megakaryoblast lineage of this leukemia. Using this model, we map fusion genome wide binding that in turn imparts the characteristic transcriptional signature. A network of transcription factor genes bound and upregulated by the fusion are found to have downstream effects that result in dysregulated signaling of developmental pathways including NOTCH, Hedgehog, TGFβ, and WNT. Transcriptional regulation is mediated by homo-dimerization and binding of the ETO transcription factor through the nervy homology region 2. Loss of nerve homology region 2 abrogated the development of leukemia, leading to downregulation of JAK/STAT, Hedgehog, and NOTCH transcriptional signatures. These data contribute to the understanding of CBFA2T3-GLIS2 mediated leukemogenesis and identify potential therapeutic vulnerabilities for future studies.

Suggested Citation

  • Elizabeth A. R. Garfinkle & Pratima Nallagatla & Binay Sahoo & Jinjun Dang & Mohammad Balood & Anitria Cotton & Camryn Franke & Sharnise Mitchell & Taylor Wilson & Tanja A. Gruber, 2024. "CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53158-9
    DOI: 10.1038/s41467-024-53158-9
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    1. Esther Ortega & Srinivasan Rengachari & Ziad Ibrahim & Naghmeh Hoghoughi & Jonathan Gaucher & Alex S. Holehouse & Saadi Khochbin & Daniel Panne, 2018. "Transcription factor dimerization activates the p300 acetyltransferase," Nature, Nature, vol. 562(7728), pages 538-544, October.
    2. Christina D. Drenberg & Anang Shelat & Jinjun Dang & Anitria Cotton & Shelley J. Orwick & Mengyu Li & Jae Yoon Jeon & Qiang Fu & Daelynn R. Buelow & Marissa Pioso & Shuiying Hu & Hiroto Inaba & Raul C, 2019. "A high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    3. Loren M. Lasko & Clarissa G. Jakob & Rohinton P. Edalji & Wei Qiu & Debra Montgomery & Enrico L. Digiammarino & T. Matt Hansen & Roberto M. Risi & Robin Frey & Vlasios Manaves & Bailin Shaw & Mikkel A, 2017. "Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours," Nature, Nature, vol. 550(7674), pages 128-132, October.
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