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1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma

Author

Listed:
  • Travis S. Johnson

    (Indiana University
    Indiana Biosciences Research Institute
    Indiana University
    Indiana University)

  • Parvathi Sudha

    (Indiana University)

  • Enze Liu

    (Indiana University)

  • Nathan Becker

    (Indiana University)

  • Sylvia Robertson

    (Indiana Biosciences Research Institute)

  • Patrick Blaney

    (New York University)

  • Gareth Morgan

    (New York University)

  • Vivek S. Chopra

    (Genentech Inc.)

  • Cedric Santos

    (Genentech Inc.)

  • Michael Nixon

    (Roche Inc.)

  • Kun Huang

    (Indiana University
    Indiana University
    Indiana University)

  • Attaya Suvannasankha

    (Indiana University
    Roudebush VAMC)

  • Mohammad Abu Zaid

    (Indiana University)

  • Rafat Abonour

    (Indiana University)

  • Brian A. Walker

    (Indiana University
    Indiana University)

Abstract

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.

Suggested Citation

  • Travis S. Johnson & Parvathi Sudha & Enze Liu & Nathan Becker & Sylvia Robertson & Patrick Blaney & Gareth Morgan & Vivek S. Chopra & Cedric Santos & Michael Nixon & Kun Huang & Attaya Suvannasankha &, 2024. "1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48327-9
    DOI: 10.1038/s41467-024-48327-9
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    References listed on IDEAS

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    1. Stephan M. Tirier & Jan-Philipp Mallm & Simon Steiger & Alexandra M. Poos & Mohamed H. S. Awwad & Nicola Giesen & Nicola Casiraghi & Hana Susak & Katharina Bauer & Anja Baumann & Lukas John & Anja Sec, 2021. "Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Rebecca Boiarsky & Nicholas J. Haradhvala & Jean-Baptiste Alberge & Romanos Sklavenitis-Pistofidis & Tarek H. Mouhieddine & Oksana Zavidij & Ming-Chieh Shih & Danielle Firer & Mendy Miller & Habib El-, 2022. "Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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