Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma

Abstract

B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma.

Uncovering the Exosomes Diversity: A Window of Opportunity for Tumor Progression Monitoring

“…The IgBCR is expressed on the surface of the B-cell membrane surface during the B-cell development, and it is responsible for antigen-binding and specific immune response. Several reports demonstrated the role of IgBCR in the pathogenesis and progression of B-cells malignancies, such as CLL [96] and MM [97], through altered signaling [98,99]. As the IgBCR expresses a specific antigen-binding site, it can be considered a tumor B-cell biomarker in the case of B-lymphoproliferative disorders.…”

Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond

“…This increases the probability that over time a single clone escapes proliferative control. Moreover, the frequency of spontaneous mutations within the genome of plasma cells has been implicated; such a condition may provide an evolutionary advantage by offering a wide panel of preformed antibodies with epitopes potentially matching previously unknown antigens, without being actually primed by mechanisms involving antigen-presenting cells or T cells [28]. This could greatly enhance the speed of Ab-mediated adaptive immune responses to a previously unknown viral or bacterial challenge.…”

Role of Polycomb Complexes in Normal and Malignant Plasma Cells

“…MM development (i.e., myelomagenesis) is a multi-step process characterized by the appearance of genomic alterations and microenvironmental changes [69,70]. MM is a highly heterogeneous disease at the molecular and clinical levels [71][72][73][74].…”