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

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Symptomatic multiple myeloma is characterized by osteolytic lesions (OL).
• The precise mechanisms by which malignant plasma cells (PC) induce bone destruction in specific areas while sparing others remain unclear.
• Understanding the heterogeneity of PC is crucial for unraveling the pathogenesis of myeloma bone disease.

Purpose of the Study:

• To investigate the heterogeneity of malignant plasma cells (PC) in multiple myeloma (MM).
• To identify molecular differences between PC from osteolytic lesions (OL) and bone marrow (BM).
• To explore transcriptional changes in PC following induction therapy.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of 148,630 PC from 24 distinct locations in 10 patients.
• Prospective collection of PC from bone marrow aspirates (BM) and paired imaging-guided biopsies of OL.
• Integrated analysis of anchored scRNA-seq datasets from BM and OL, including longitudinal samples.

Main Results:

• Observed extensive inter- and intra-patient heterogeneity in PC based on scRNA-seq.
• Identified differentially expressed genes in PC from OL compared to BM.
• Upregulation of DKK1, HGF, and TIMP-1, and downregulation of JUN/FOS, DUSP1, and HBB in OL-derived PC.
• Detected transcriptional alterations in PC after induction therapy.

Conclusions:

• Single-cell RNA sequencing reveals significant spatial and molecular heterogeneity in multiple myeloma plasma cells.
• Distinct gene expression profiles in PC from osteolytic lesions contribute to myeloma bone disease.
• This heterogeneity offers new insights into the mechanisms of destructive bone disease in multiple myeloma.