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 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.

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.…”

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma

“…It can be observed not only during the disease course as an adaptation to different treatments, but also at the same time point of the disease stage with different clones being present at different locations of the body (e.g., in focal lesions and the iliac crest; 28 ). Even within a compartment, such as the bone marrow, the expression pattern of plasma cells can differ depending on their position ( 29 ). Adding further complexity is the fact that the patient’s treatment course can be especially heterogeneous regarding the sequence of therapeutic regimes the patient received.…”

Mapping Intrapatient Response Heterogeneity and Lesion-specific Relapse Dynamics in Metastatic Colorectal Cancer

“…Most investigations of intrapatient lesion 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 intrapatient response heterogeneity 11,12 .…”