Abstract
Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies.
Highlights
MicroRNAs are short noncoding RNAs that regulate gene expression by repressing messenger RNA translation or inducing its degradation.[1]
During TD activation, Fo B cells form germinal centers (GCs) and undergo affinity maturation during the GC reaction, a process regulated by several miRs including miR-155, miR-125b, miR-28, and miR-217.9-13 the GC reaction is essential for normal acquired immunity and generation of plasma cells (PCs), it substantially increases the risk of aberrant gene mutations resulting in lymphomagenesis due to ongoing activationinduced cytidine deaminase (AID)-driven somatic hypermutation and class-switch recombination, associated with tolerance for DNA damage and high proliferation.[14,15]
We showed that most of the miR-15a and miR-16 signal comes from CD101 GC B cells and not T-follicular helper cells or PCs residing within GCs
Summary
MicroRNAs (miRs) are short noncoding RNAs that regulate gene expression by repressing messenger RNA (mRNA) translation or inducing its degradation.[1]. T-cell–independent (TI) activation.[7,8] During TD activation, Fo B cells form germinal centers (GCs) and undergo affinity maturation during the GC reaction, a process regulated by several miRs including miR-155, miR-125b, miR-28, and miR-217.9-13 the GC reaction is essential for normal acquired immunity and generation of plasma cells (PCs), it substantially increases the risk of aberrant gene mutations resulting in lymphomagenesis due to ongoing activationinduced cytidine deaminase (AID)-driven somatic hypermutation and class-switch recombination, associated with tolerance for DNA damage and high proliferation.[14,15] This is evidenced by the GC or post-GC origin of most B-cell lymphomas.[14,16]
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