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

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 the first 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 analyzed 148,630 PC from 24 different locations in 10 patients and observed vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we found an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL were 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 revealed transcriptional changes after induction therapy. Our study, based on the largest number of PC analyzed by scRNA-seq, contributes to the understanding of destructive myeloma bone disease.

Whole‐body magnetic resonance imaging plus serological follow‐up for early identification of progression in smouldering myeloma patients to prevent development of end‐organ damage

“…In most settings economic reasons will prevent the more frequent use of MRI than every 6 months; however, further identification of accompanying clinical and serological markers in larger studies might provide tools guiding a more individualized use of modern imaging techniques. The fact that some lesions developed in a short period of time, while other disease markers were stable or showed only slow progression, supports the observation that myeloma cells can show different biological behaviour in different areas of the bone marrow, 34 especially when it comes to bone disease 35 …”

“…fact that some lesions developed in a short period of time, while other disease markers were stable or showed only slow progression, supports the observation that myeloma cells can show different biological behaviour in different areas of the bone marrow, 34 especially when it comes to bone disease. 35 Even within the group of patients which are now considered SMM, further risk stratification is of interest to select high-risk patients for clinical trials, and new IMWG criteria for high-risk SMM have been established. 26,36 In the current study we also investigated the influence of having exactly one FL in MRI, and we analysed whether these new criteria are also connected to adverse outcome when they occur during follow-up.…”

Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma

“…Single cell RNA sequencing (scRNA-seq) has been successfully used to study cellular dynamics associated with response to CD19directed CAR T cell therapy in large B cell lymphoma and acute lymphoblastic leukemia [10][11][12] . Furthermore, single cell sequencing has shed new light on the evolution of asymptomatic plasma cell disorders, over symptomatic disease to RRMM [13][14][15][16][17] . Single cell sequencing offers the unique opportunity to study the interplay between CAR T cells, malignant plasma cells and non-malignant cells of the host immune microenvironment.…”

Mapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer

“…Most investigations of metastatic heterogeneity focus on tumor genetic mutations, clonal compositions, or transcriptomics [8][9][10] . These molecular and cellular characterizations are critical to elucidating the underlying mechanisms of lesion response heterogeneity 11,12 .…”