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Single Cell RNA Sequencing Before and After Light Chain Escape Reveals Intra-patientMultiple Myeloma Subpopulations with Divergent Osteolytic Gene Expression

ABSTRACT: Single Cell RNA Sequencing Before and After Light Chain Escape Reveals Intra-patientMultiple Myeloma Subpopulations with Divergent Osteolytic Gene Expression

PROVIDER: PRJNA1183885 | ENA |

REPOSITORIES: ENA

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Single Cell RNA Sequencing Before and After Light Chain Escape Reveals Intra-patientMultiple Myeloma Subpopulations with Divergent Osteolytic Gene Expression

Project description:High-risk multiple myeloma (MM) is genomically unstable, comprised of heterogeneous populations of tumor cells that evolve over time. Lightchain escape (LCE) is a clinical phenomenon observed when light chains rise separately from M-spike values, implying divergent tumor evolution. We sought to understand LCE by performing high depth transcriptomic and phenotypic studies. We performed single cell RNA sequencing and ex vivo drug sensitivity profiling on serial bone marrow biopsies from a patient with LCE at diagnosis, first relapse and relapsed/refractory timepoints. Single cell RNA sequencing uncovered distinct transcriptomic subpopulations with phenotypes that could be tracked separately by clinical serum light chain and M-spike values. Genes differentially expressed between subpopulations were assessed for generalizable effects on prognosis from the MMRF CoMMpass and GSE24080 datasets. Notably ,the LCE subpopulation exhibited gene expression profile featuring prominentLAMP5-overexpression, which was associated with risk for osteolytic bone lesions. Ex vivo drug sensitivity testing displayed differential sensitivity of the subpopulations. Copy Number Variant inference showed that the transcriptomic subpopulation underlying LCE was related to a genetic subclone that evolved overtime. Our findings illustrate that malignant subpopulations underly light chain escape in multiple myeloma. These studies implied that LCE and LAMP5 gene overexpression portends for increased risk of osteolytic bone disease and adverse prognosis, findings that were confirmed in the subset of patients in the CoMMpass database with light chain escape.

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Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanism underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remains unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent, or treat patients with, myeloma bone disease.

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