Abstract

B lymphocyte differentiation is an exquisitely regulated homeostatic process resulting in continuous production of appropriately selected B cells. Relatively small changes in gene expression can result in deregulation of this process, leading to acute lymphocytic leukemia (ALL), immune deficiency, or autoimmunity. Translocation of MLL1 (KMT2A) often results in a pro-B cell ALL, but little is known about its role in normal B cell differentiation. Using a Rag1-cre mouse knock-in to selectively delete Mll1 in developing lymphocytes, we show that B cell, but not T cell, homeostasis depends on MLL1. Mll1−/− B progenitors fail to differentiate efficiently through the pro- to pre-B cell transition, resulting in a persistent reduction in B cell populations. Cells inefficiently transit the pre-BCR checkpoint, despite normal to higher levels of pre-BCR components, and rearranged IgH expression fails to rescue this differentiation block. Instead of IgH-rearrangement defects, we find that Mll1−/− pre-B cells exhibit attenuated RAS/MAPK signaling downstream of the pre-BCR, which results in reduced survival in physiologic levels of IL-7. Genome-wide expression data illustrate that MLL1 is connected to B cell differentiation and IL-7–dependent survival through a complex transcriptional network. Overall, our data demonstrate that wild-type MLL1 is a regulator of pre-BCR signaling and B cell differentiation and further suggest that targeting its function in pro-B cell ALL may be more broadly effective than previously anticipated.