Abstract
B cell development in bone marrow (BM) is a multi-staged process involving pro-B, pre-B, immature B, and mature B cells, among which pre-B cells undergo vigorous proliferation, differentiation, apoptosis, and gene rearrangement. While several signaling pathways participate in pre-B cell development have been clarified, detailed intrinsic mechanisms regulating pre-B cell proliferation and survival have not been fully understood. In the current study, we report that miR-582 regulates pre-B cell proliferation and survival. miR-582 is enriched in pre-B cells. Deletion of miR-582 in mice expanded the BM pre-B cell population in a cell-autonomous manner as shown by competitive BM transplantation. We show that forced miR-582 overexpression inhibited pre-B cell proliferation and survival, whereas downregulation of miR-582 by siRNA significantly promoted pre-B cell proliferation and survival in vitro. We identified that Hif1α and Rictor are authentic targets of miR-582 in pre-B cells as shown by reporter assays. Moreover, miR-582 overexpression reduced the expression of Hif1α and its downstream molecule Glut1, as well as Rictor and mTORC2 activity as shown by attenuated AKT and FoxO1 phosphorylation, while miR-582 knockdown showed opposite effects. miR-582 knockdown-induced increases in pre-B proliferation and survival was abrogated by Hif1α and Rictor inhibitors. Together, miR-582 functions as a negative regulator of pre-B cell proliferation and survival by simultaneously targeting Hif1α and mTORC2 signaling that regulates metabolism in early B cell development.
Highlights
B lymphocytes (B cells) are pivotal adaptive immune cells that mediate the humoral arm of immune responses against pathogens and mutant cells by secreting antibodies that recognize and bind antigens [1]
Pro-B, pre-B, immature-B, and mature-B cells were sorted from bone marrow (BM) and spleen, and the expression of miR-5825p, miR-582-3p, and Pde4d mRNA was determined by qRT-polymerase chain reaction (PCR)
We have found that miR-582 is essential for inhibiting excessive proliferation of pre-B cells during B cell development in BM
Summary
B lymphocytes (B cells) are pivotal adaptive immune cells that mediate the humoral arm of immune responses against pathogens and mutant cells by secreting antibodies that recognize and bind antigens [1]. HSCs differentiate into common lymphoid progenitors (CLPs), which select a B cell fate by initiating the consecutive process of DNA recombination of B cell receptor (BCR) genes to generate a specific BCR for each B cell clone [3, 4]. This process is accompanied by staged B cell development including pro-B, pre-B, immature and mature B cells, during which cell proliferation, differentiation, as well as clonal selection take place to guarantee the formation of a proper peripheral B cell repertoire [5]. Elucidating mechanisms regulating pre-B cell proliferation and survival is one of the research focuses for understanding B cell development and related human malignancies such as certain types of B cell lymphoma
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