miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms

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 the del(13q), suggesting an 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 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 which has progressed to extramedullary disease. We corroborate that human primary EP have 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.

Genetics of Chronic Lymphocytic Leukemia

“…The most frequent genetic lesions in CLL (approximately 50%-60% of patients) 45 are deletions of 13q14 (del13q14), which are generally monoallelic (approximately 80% of del13q14 events), more prevalent in the IGHV-M subgroup than in IGHV-UM CLLs, and associated with a good prognosis. 36,[45][46][47] These lesions are often the unique cytogenetic abnormality of CLL and have also been found in plasma cell neoplasms and other tumors, 48,49 in agreement with their presumed role in the pathogenesis of early-stage CLL. 36,45,46 While the extent of deletions is extremely variable, the minimal deleted region, that is, the region that is consistently lost in all CLL cases with 13q14 lesions, contains 2 long noncoding RNA genes (DLEU2 and DLEU1 and the microRNA gene cluster MIR15A-MIR16-1).…”

“…The most frequent genetic lesions in CLL (approximately 50%–60% of patients) 45 are deletions of 13q14 (del13q14), which are generally monoallelic (approximately 80% of del13q14 events), more prevalent in the IGHV -M subgroup than in IGHV -UM CLLs, and associated with a good prognosis 36,45–47 . These lesions are often the unique cytogenetic abnormality of CLL and have also been found in plasma cell neoplasms and other tumors, 48,49 in agreement with their presumed role in the pathogenesis of early-stage CLL 36,45,46 .…”

Optimized workflow to modify microRNA expression in primary human intravascular cells

“…Deletion or silencing of miR-15a/16-1 cluster is found in several blood disorders in humans [ 26 – 28 ]. Deletion of miR-15a/16-1 cluster results in blood disorders in mice confirming the causative role of miR-15a/16-1 in human diseases and highlighting the role of miRNA cluster in functional regulation of blood cells [ 29 – 31 ]. The physiological role of miR-15a/16-1 is, however, tissue-specific as endothelium-specific deletion of miR-15a/16-1 cluster improves brain function and blood–brain barrier structure after brain injury [ 21 , 22 ].…”

A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer

“…BCL9/9L-KO signature components by Moor et al ( 53 ) were used as BCL9/B9L signature. GSEA of these and the Hallmark MSigDB gene sets ( 51 ) was performed using recommended settings as previously described ( 82 , 83 ). Data were visualized as previously described ( 83 ).…”

“…BCL9/9L-KO signature components by Moor et al (53) were used as BCL9/B9L signature. GSEA of these and the Hallmark MSigDB gene sets (51) was performed using recommended settings as previously described (82,83). Data were visualized as previously described (83).…”