Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma

Maximilian Merz (), Almuth Maria Anni Merz, Jie Wang, Lei Wei, Qiang Hu, Nicholas Hutson, Cherie Rondeau, Kimberly Celotto, Ahmed Belal, Ronald Alberico, AnneMarie W. Block, Hemn Mohammadpour, Paul K. Wallace, Joseph Tario, Jesse Luce, Sean T. Glenn, Prashant Singh, Megan M. Herr, Theresa Hahn, Mehmet Samur, Nikhil Munshi, Song Liu, Philip L. McCarthy and Jens Hillengass ()
Additional contact information
Maximilian Merz: Roswell Park Comprehensive Cancer Center (Roswell Park)
Almuth Maria Anni Merz: Roswell Park Comprehensive Cancer Center (Roswell Park)
Jie Wang: Roswell Park
Lei Wei: Roswell Park
Qiang Hu: Roswell Park
Nicholas Hutson: Roswell Park
Cherie Rondeau: Roswell Park Comprehensive Cancer Center (Roswell Park)
Kimberly Celotto: Roswell Park Comprehensive Cancer Center (Roswell Park)
Ahmed Belal: Roswell Park
Ronald Alberico: Roswell Park
AnneMarie W. Block: Roswell Park
Hemn Mohammadpour: Roswell Park
Paul K. Wallace: Roswell Park
Joseph Tario: Roswell Park
Jesse Luce: Roswell Park
Sean T. Glenn: Roswell Park
Prashant Singh: Roswell Park
Megan M. Herr: Roswell Park
Theresa Hahn: Roswell Park
Mehmet Samur: Dana Farber Cancer Institute
Nikhil Munshi: Harvard Medical School
Song Liu: Roswell Park
Philip L. McCarthy: Roswell Park
Jens Hillengass: Roswell Park Comprehensive Cancer Center (Roswell Park)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease.

Date: 2022
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DOI: 10.1038/s41467-022-28266-z

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