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

Published in Nature Communications. Here is a link to the article.

Regenstrief Institute authors: Kun Huang, PhD

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.

Authors

Travis S. Johnson^1,2,3,4, Parvathi Sudha⁵, Enze Liu⁵, Nathan Becker⁵, Sylvia Robertson², Patrick Blaney⁶, Gareth Morgan⁶, Vivek S Chopra⁷, Cedric Dos Santos⁷, Michael Nixon⁸, Kun Huang^1,3,4, Attaya Suvannasankha^5,9, Mohammad Abu Zaid⁵, Rafat Abonour⁵, Brian A Walker^10,11

Affiliations

¹Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN, USA.

²Indiana Biosciences Research Institute, Indianapolis, IN, USA.

³Melvin and Bren Simon Comprehensive Cancer Center, Experimental and Developmental Therapeutics, School of Medicine, Indiana University, Indianapolis, IN, USA.

⁴Center for Computational Biology and Bioinformatics, School of Medicine, Indiana University, Indianapolis, IN, USA.

⁵Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana University, Indianapolis, IN, USA.

⁶Perlmutter Cancer Center, Langone Health, New York University, New York, NY, USA.

⁷Genentech Inc., South San Francisco, CA, USA.

⁸Roche Inc., Indianapolis, IN, USA.

⁹Roudebush VAMC, Indianapolis, IN, USA.

¹⁰Center for Computational Biology and Bioinformatics, School of Medicine, Indiana University, Indianapolis, IN, USA. bw75@iu.edu.

¹¹Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana University, Indianapolis, IN, USA. bw75@iu.edu.