The role of IL-7 in guiding developing B cells through the pre-B cell check-point

New York University School Of Medicine, New York NY

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Abstract

DESCRIPTION (provided by applicant): Pre-B cells are subject to transformation as they transition from highly proliferative large pre-B cells to small pre- B cells that acquire multiple double-stranded breaks during the process of light-chain recombination. Modulation of IL-7, a cytokine that is expressed by a subset of bone marrow stromal cells, promotes light-chain recombination and cell cycle exit at the pre-B cell stage. Though it has been shown that inappropriate IL-7 signals can lead to the formation of leukemia, little is known regarding the mechanisms by which IL-7 signaling guides cells through this developmental check-point. In addition, it is not clear how a developing pre-B cell is brought to an appropriate environmental niche within the bone marrow such that it is properly exposed to IL-7 in vivo. Our preliminary data demonstrates that STATS, a downstream signaling molecule in the related IL-7 and TSLP signaling pathways, directly targets the kappa light-chain and RAG loci at the pre-B cell stage, leading to their repression. Intriguingly, our data suggests that the necessary attenuation of IL-7 that occurs in order to promote developmental progression of the B cell lineage is the result of altered pre-B cell migration patterns that move developing cells away from IL-7 expressing stroma. In this proposal, using a variety of genetically engineered animals I will investigate the molecular mechanisms by which STAT5 restricts immunoglobulin light-chain recombination to the pre-B cell stage, thereby preventing uncontrolled DNA damage. Specifically, I will explore mechanisms that include competitive binding and altered locus accessibility considering both localized changes in chromatin structure as well as more global changes in nuclear localization. In addition, I will examine the components that control pre-B cell migration patterns relative to IL-7 expressing stroma within the bone marrow, thereby enabling cells to receive appropriate signals. I will examine the requirement of the transcription factor IRF-4 in this process as well as the chemokine receptor CXCR4. As a long-term goal I will also explore pre-B cell migration patterns in real time using the 2-photon system. This work will reveal, at both the molecular and cellular level, how key developmentally regulated signaling pathways control passage through the pre-BCR checkpoint, thereby lowering the possibility of cell transformation. Relevance: Developing B cells are subject to genomic instability and transformation during the process of antigen receptor rearrangement. This proposal aims to: 1) define the molecular mechanisms by which a key environmental signaling pathway guides recombination and 2) uncover the components responsible for directing developing pre-B cells to the proper environmental niche such that appropriate signaling can occur. Ultimately, this work will lead to the generation of new therapeutic targets for the treatment of B cell ALL.