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Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting

Author

Listed:
  • Yasuo Kubota

    (Taussig Cancer Institute, Cleveland Clinic)

  • Xiaorong Gu

    (Taussig Cancer Institute, Cleveland Clinic)

  • Laila Terkawi

    (Taussig Cancer Institute, Cleveland Clinic)

  • Juraj Bodo

    (Cleveland Clinic)

  • Bartlomiej P. Przychodzen

    (Taussig Cancer Institute, Cleveland Clinic)

  • Hussein Awada

    (Taussig Cancer Institute, Cleveland Clinic)

  • Nakisha Williams

    (Taussig Cancer Institute, Cleveland Clinic)

  • Carmelo Gurnari

    (Taussig Cancer Institute, Cleveland Clinic
    University of Rome Tor Vergata)

  • Naomi Kawashima

    (Taussig Cancer Institute, Cleveland Clinic)

  • Mai Aly

    (Taussig Cancer Institute, Cleveland Clinic)

  • Arda Durmaz

    (Taussig Cancer Institute, Cleveland Clinic)

  • Minako Mori

    (Taussig Cancer Institute, Cleveland Clinic)

  • Ben Ponvilawan

    (Taussig Cancer Institute, Cleveland Clinic)

  • Tariq Kewan

    (Taussig Cancer Institute, Cleveland Clinic)

  • Waled Bahaj

    (Taussig Cancer Institute, Cleveland Clinic)

  • Manja Meggendorfer

    (MLL Munich Leukemia Laboratory)

  • Babal K. Jha

    (Taussig Cancer Institute, Cleveland Clinic
    Lerner Research Institute (LRI) Cleveland Clinic)

  • Valeria Visconte

    (Taussig Cancer Institute, Cleveland Clinic)

  • Heesun J. Rogers

    (Cleveland Clinic)

  • Torsten Haferlach

    (MLL Munich Leukemia Laboratory)

  • Jaroslaw P. Maciejewski

    (Taussig Cancer Institute, Cleveland Clinic)

Abstract

PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.

Suggested Citation

  • Yasuo Kubota & Xiaorong Gu & Laila Terkawi & Juraj Bodo & Bartlomiej P. Przychodzen & Hussein Awada & Nakisha Williams & Carmelo Gurnari & Naomi Kawashima & Mai Aly & Arda Durmaz & Minako Mori & Ben P, 2024. "Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46134-w
    DOI: 10.1038/s41467-024-46134-w
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    References listed on IDEAS

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    1. Jeffrey W. Tyner & Cristina E. Tognon & Daniel Bottomly & Beth Wilmot & Stephen E. Kurtz & Samantha L. Savage & Nicola Long & Anna Reister Schultz & Elie Traer & Melissa Abel & Anupriya Agarwal & Auro, 2018. "Functional genomic landscape of acute myeloid leukaemia," Nature, Nature, vol. 562(7728), pages 526-531, October.
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