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Accession IconGSE108093

MLL1 promotes IL-7 responsiveness and survival during B cell differentiation

Organism Icon Mus musculus
Sample Icon 8 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Genome 430 2.0 Array (mouse4302)

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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 acute lymphocytic leukemia, immune deficiency or autoimmunity. Translocation of Mll1 (Kmt2a) often results in a pro-B cell acute lymphocytic leukemia (B-ALL), but little is known about its role in normal B cell differentiation. Using a Rag1-cre 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-B cell receptor (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, resulting 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 B-ALL may be more broadly effective than previously anticipated.
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