The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

Abstract

Pleiotropic functions of miRNAs as transcriptional repressors have been reported for multiple biological processes. One prominent miRNA family is the miR-15 family, which is a well-established tumor-suppressor in chronic lymphocytic leukemia. The miR-15 family consists of three bicistronic clusters, all sharing the same seed sequence suggesting that loss of one cluster can be functionally compensated by the remaining miR-15 family members. Thus, a combined deletion may be necessary to reveal its physiological function in vivo. A combined knockout of the most prominent miR-15 clusters, miR-15a/16-1 and miR-15b/16-2 reveals a novel role in early B cell development highlighted by increasing the pro-B cell compartment. Mechanistically, this effect is mediated by enhanced IL-7 receptor expression. Notably, elevated IL-7 receptor levels were sufficient to trigger increased activation of the STAT5 and PI3K/AKT pathways. Moreover, derepression of cell cycle regulators such as Ccne1, Chek1 and Wee1 further facilitates G-to-S transition. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu manifesting in an enlarged pro-B cell pool.