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

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, Mohammad Abu Zaid, Rafat Abonour and Brian A. Walker ()
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Travis S. Johnson: 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
Attaya Suvannasankha: Indiana University
Mohammad Abu Zaid: Indiana University
Rafat Abonour: Indiana University
Brian A. Walker: Indiana University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48327-9

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