Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics

Abstract

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.

Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease

“…In contrast, xenografts in untreated mice showed enhanced tumor growth and increased VEGF blood concentrations (62). In line with these findings, transcriptomic profiling of the immune cell compartment in patients suffering from refractory or relapsed myeloma, revealed enrichment of a distinct subset of macrophages expressing genes linked to angiogenesis such as VEGF-A or diphtheria toxin receptor (Heparin-Binding EGF-Like Growth Factor) (63). BMI1, a member of a polycomb group multiprotein complex, is overexpressed in macrophages of 5Tmyeloma mice compared to macrophages derived from healthy mice.…”

IgE type multiple myeloma exhibits hypermutated phenotype and tumor reactive T cells

“…To further characterize genomic and microenvironmental characteristics of IgE type MM, we performed WGS analysis of CD138 + aberrant plasma cells as well as single-cell RNA profiling of bone marrow-derived mononuclear cells including aberrant plasma cells and CD45 + immune cells, as well as peripheral blood mononuclear cells (PBMCs) to assess putative immunological effects of disease activity including excessive systemic IgE levels. We analyzed IgE kappa MM bone marrow aspirate on a genomic and microenvironmental level by integrating DNA- and single-cell RNA sequencing and comparative profiling against non-IgE type RRMM samples 10 ( figure 2A ). IgE type MM cells demonstrated a distinct transcriptional profile including homogenous Immunoglobulin Heavy Constant Epsilon (IGHE) expression in comparison to non-IgE type MM cells, therefore, separating as distinct entity in Uniform Manifold Approximation and Projection (UMAP)-guided clustering ( figure 2A , online supplemental figure 1a ).…”

Single‐cell RNA‐seq reveals clonal diversity and prognostic genes of relapsed multiple myeloma

“…36 To identify the overlap genes between our study and previous reports, we performed an integrated comparative analysis between DEGs in each cluster (Table S9 and Figure S20). 16,33,36,57 We identified a slight overlap between our DEGs and other signature genes, which included a set of 14 genes increased expression in both clusters 2&6 and the 'PMID33619369 Resistance signature 1', indicating that both oxidative phosphorylation (i.e. COX8A, COX6A1, NDUFB2, COX7B and NDUFS6) and glycolysis/gluconeogenesis (i.e.…”