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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 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.

SUBMITTER: Sewastianik T

PROVIDER: S-EPMC8033455 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleAngiogenesis promotes neurological recovery after stroke and is associated with longer survival of stroke patients. Cerebral angiogenesis is tightly controlled by certain microRNAs (miRs), such as the miR-15a/16-1 cluster, among others. However, the function of the miR-15a/16-1 cluster in endothelium on postischemic cerebral angiogenesis is not known.ObjectiveTo investigate the functional significance and molecular mechanism of endothelial miR-15a/16-1 cluster on angiogenesis in the ischemic brain.Methods and resultsEndothelial cell-selective miR-15a/16-1 conditional knockout (EC-miR-15a/16-1 cKO) mice and wild-type littermate controls were subjected to 1 hour middle cerebral artery occlusion followed by 28-day reperfusion. Deletion of miR-15a/16-1 cluster in endothelium attenuates post-stroke brain infarction and atrophy and improves the long-term sensorimotor and cognitive recovery against ischemic stroke. Endothelium-targeted deletion of the miR-15a/16-1 cluster also enhances post-stroke angiogenesis by promoting vascular remodeling and stimulating the generation of newly formed functional vessels, and increases the ipsilateral cerebral blood flow. Endothelial cell-selective deletion of the miR-15a/16-1 cluster up-regulated the protein expression of pro-angiogenic factors VEGFA (vascular endothelial growth factor), FGF2 (fibroblast growth factor 2), and their receptors VEGFR2 (vascular endothelial growth factor receptor 2) and FGFR1 (fibroblast growth factor receptor 1) after ischemic stroke. Consistently, lentiviral knockdown of the miR-15a/16-1 cluster in primary mouse or human brain microvascular endothelial cell cultures enhanced in vitro angiogenesis and up-regulated pro-angiogenic proteins expression after oxygen-glucose deprivation, whereas lentiviral overexpression of the miR-15a/16-1 cluster suppressed in vitro angiogenesis and down-regulated pro-angiogenic proteins expression. Mechanistically, miR-15a/16-1 translationally represses pro-angiogenic factors VEGFA, FGF2, and their receptors VEGFR2 and FGFR1, respectively, by directly binding to the complementary sequences within 3'-untranslated regions of those messenger RNAs.ConclusionsEndothelial miR-15a/16-1 cluster is a negative regulator for postischemic cerebral angiogenesis and long-term neurological recovery. Inhibition of miR-15a/16-1 function in cerebrovascular endothelium may be a legitimate therapeutic approach for stroke recovery.

Project description:MicroRNAs are small non-coding RNAs that have emerged as post-transcriptional regulators involved in development and function of different types of immune cells, and aberrant miRNA expression has often been linked to cancer. One prominent miRNA family in the latter setting is the miR-15 family, consisting of the three clusters miR-15a/16-1, miR-15b/16-2 and miR-497/195, which is best known for its prominent tumor suppressive role in chronic lymphocytic leukemia (CLL). However, little is known about the physiological role of the miR-15 family. In this study, we provide a comprehensive in vivo analysis of the physiological functions of miR-15a/16-1 and miR-15b/16-2, both of which are highly expressed in immune cells, in early B cell development. In particular, we report a previously unrecognized physiological function of the miR-15 family in restraining progenitor B cell expansion, as loss of both clusters induces an increase of the pro-B as well as pre-B cell compartments. Mechanistically, we find that the miR-15 family mediates its function through repression of at least two different types of target genes: First, we confirm that the miR-15 family suppresses several prominent cell cycle regulators such as Ccne1, Ccnd3 and Cdc25a also in vivo, thereby limiting the proliferation of progenitor B cells. Second, this is complemented by direct repression of the Il7r gene, which encodes the alpha chain of the IL-7 receptor (IL7R), one of the most critical growth factor receptors for early B cell development. In consequence, deletion of the miR-15a/16-1 and miR-15b/16-2 clusters stabilizes Il7r transcripts, resulting in enhanced IL7R surface expression. Consistently, our data show an increased activation of PI3K/AKT, a key signaling pathway downstream of the IL7R, which likely drives the progenitor B cell expansion we describe here. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu that manifests in an enlarged progenitor B cell pool.

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

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