Pathogenesis beyond the cancer clone(s) in multiple myeloma

Abstract

Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. (Blood. 2015;125(20):3049-3058) Characteristics of the myeloma cancer clone Ontogenesis of myelomaMultiple myeloma (MM) represents the far end of the spectrum of B cell-derived neoplasms. It is the neoplastic counterpart of terminally differentiated, immunoglobulin-producing, long-lived plasma cells (PCs). Long-lived PCs are a subset of PCs characterized by long-term (months to years) survival within the bone marrow (BM) and thought to be key for immunologic memory.1,2 Based on the sequencing of the immunoglobulin heavy chain (IgH) variable region of MM cells (MMCs), the first oncogenic events in MM appear to occur in the germinal center, likely during the processes of isotype class switching and somatic hypermutation, which are, by nature, mutation prone. 3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC (Figure 1). 4 There is ongoing debate regarding the identity of the MM stem cells. Different groups have shown that both CD138 1 and CD192 cells are capable of tumorigenesis in mouse models.However, CD138 1 tends to lose self-renewing potential after a few cycles of serial transplantation, whereas the putative B-cell stem clone was never proved to be clonally related to its putative CD138 1 progeny.Overall, modification in the cytokine composition of the media used to maintain CD138 1 ex vivo successfully overcame the first issue, suggesting that the MM stem cell may be CD1381 . 5Ev...

Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

“…Despite the fact that knowledge about the biology of MM PCs has greatly increased in recent years, 1 the same does not apply to AL. Thus, the cytogenetic profile of patients with AL has only been reported in a few studies [2][3][4][5][6][7] that investigated a limited number of alterations (eg, IGH translocations or 13q and 17p deletion).…”

Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss

“…1 Osteolytic lesions are a hallmark of this disease, and the loss of bone is largely caused by increased osteoclast activity.…”

Newly established myeloma-derived stromal cell line MSP-1 supports multiple myeloma proliferation, migration, and adhesion and induces drug resistance more than normal-derived stroma

“…4 It was also shown that normal or MM-derived exosomes differentially affect MM cell homing and growth in vivo. 15 Altogether, these studies warrant the need for a better understanding of the role of the malignant BM microenvironment in MM.…”