Abstract
We used single cell RNA-Seq to examine molecular heterogeneity in multiple myeloma (MM) in 597 CD138 positive cells from bone marrow aspirates of 15 patients at different stages of disease progression. 790 genes were selected by coefficient of variation (CV) method and organized cells into four groups (L1–L4) using unsupervised clustering. Plasma cells from each patient clustered into at least two groups based on gene expression signature. The L1 group contained cells from all MGUS patients having the lowest expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathways (p < 1.2 × 10−14). In contrast, the expression level of these pathway genes increased progressively and were the highest in L4 group containing only cells from MM patients with t(4;14) translocations. A 44 genes signature of consistently overexpressed genes among the four groups was associated with poorer overall survival in MM patients (APEX trial, p < 0.0001; HR, 1.83; 95% CI, 1.33–2.52), particularly those treated with bortezomib (p < 0.0001; HR, 2.00; 95% CI, 1.39–2.89). Our study, using single cell RNA-Seq, identified the most significantly affected molecular pathways during MM progression and provided a novel signature predictive of patient prognosis and treatment stratification.
Highlights
Multiple myeloma (MM) is a malignant hematological disorder characterized by the accumulation of terminally differentiated antibody-secreting plasma cells with clonal genetic/cytogenetic abnormalities that home to the bone marrow[1,2,3]
Extensive immunophenotypic and differential gene expression analyses have shown that monoclonal gammopathy of undetermined significance (MGUS) and MM can be distinguished from normal plasma cells but not from each other[4]
Patient population and clinical status Our scRNA-Seq analysis included CD138-positive cells isolated from bone aspirates of patients with MGUS (n = 3), smoldering multiple myeloma (SMM) (n = 4), newly diagnosed MM (NDMM) = 5, and refractory MM (RRMM) (n = 3)
Summary
Multiple myeloma (MM) is a malignant hematological disorder characterized by the accumulation of terminally differentiated antibody-secreting plasma cells with clonal genetic/cytogenetic abnormalities that home to the bone marrow[1,2,3]. Extensive immunophenotypic and differential gene expression analyses have shown that MGUS and MM can be distinguished from normal plasma cells but not from each other[4]. Fluorescence in situ hybridization (FISH) studies of neoplastic plasma cells demonstrate trisomies of multiple. RNA-Seq (scRNA-Seq) technology offers an opportunity for an unbiased gene expression profiling of plasma cells obtained from each patient to understand the pathogenesis of MM progression that can better guide patient. Sample IDs Total number of Total number of cells L 1 L2 L3 L4. Cytogenetic abnormality cells sequenced passing QC and information analyzed IgM MGUS1 26 IgM MGUS3 33
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