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Pathogenesis and treatment of multiple myeloma.

ABSTRACT: Multiple myeloma (MM) is the second-ranking malignancy in hematological tumors. The pathogenesis of MM is complex with high heterogeneity, and the development of the disease is a multistep process. Chromosomal translocations, aneuploidy, genetic mutations, and epigenetic aberrations are essential in disease initiation and progression. The correlation between MM cells and the bone marrow microenvironment is associated with the survival, progression, migration, and drug resistance of MM cells. In recent decades, there has been a significant change in the paradigm for the management of MM. With the development of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, chimeric antigen receptor T-cell therapies, and novel agents, the survival of MM patients has been significantly improved. In addition, nanotechnology acts as both a nanocarrier and a treatment tool for MM. The properties and responsive conditions of nanomedicine can be tailored to reach different goals. Nanomedicine with a precise targeting property has offered great potential for drug delivery and assisted in tumor immunotherapy. In this review, we summarize the pathogenesis and current treatment options of MM, then overview recent advances in nanomedicine-based systems, aiming to provide more insights into the treatment of MM.

SUBMITTER: Yang P

PROVIDER: S-EPMC9162151 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Pathogenesis and treatment of multiple myeloma.

Yang Peipei P Qu Ying Y Wang Mengyao M Chu Bingyang B Chen Wen W Zheng Yuhuan Y Niu Ting T Qian Zhiyong Z

MedComm 20220602 2

Multiple myeloma (MM) is the second-ranking malignancy in hematological tumors. The pathogenesis of MM is complex with high heterogeneity, and the development of the disease is a multistep process. Chromosomal translocations, aneuploidy, genetic mutations, and epigenetic aberrations are essential in disease initiation and progression. The correlation between MM cells and the bone marrow microenvironment is associated with the survival, progression, migration, and drug resistance of MM cells. In ...[more]

PMID: 35665368

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Project description:BackgroundDespite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals.ObjectiveWe reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role.MethodsThere were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs).ResultsSPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs.ConclusionFDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients.

Project description:Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes.SignificanceEphrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Dataset Information

Pathogenesis and treatment of multiple myeloma.

Publications

Pathogenesis and treatment of multiple myeloma.

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