In this revised renewal application we seek continued support to test the overall model that, different from adult bone marrow, B cell development in the fetal liver occurs in a distinctive hematopoietic process and proceeds by novel modes of selection. In the past grant period we have established a rigorous framework for delineating early B lineage fractions, before the pro-B (CD19+) stage. Now we will ask whether novel lineage restrictions characterize the pre-pro-B stage in fetal liver and seek to determine key gene expression differences mediating the fetal/adult switch in B lymphopoiesis (Aim 1). Based on differences in pre-B proliferation induced by heavy chain expression in fetal and adult precursors that we have observed, we will study pre-BCR signaling, asking whether it selectively activates apoptosis in fetal precursors, test how it is altered by pharmacologic inhibitors of known signaling pathways, determine its activity in Btk- deficient precursors, and analyze how it synergizes with cytokine signaling pathways (Aim 2). Finally, we will characterize panels of VDJ-mu heavy chains isolated from fetal and adult pre-B cells, for their capacity to associate with surrogate light chain, their ability to mediate changes in gene expression required for normal B lineage progression, and their competence in fostering B cell development (Aim 3). Our work will combine state-of-the-art digital flow cytometry with new methodologies for recognizing gene expression patterns in microrarray analysis and utilize retroviral provision of activating or inhibitory molecules in normal and mutant mouse progenitor populations to carry out these studies. Its completion will provide a comprehensive portrait of B cell development, contrasting its modes during fetal and adult time, with implications in the area of stem cell transplantation, neonatal immunity, and the origins of B cell subsets. Understanding the fetal generation of CD5+ B cells, with a surface phenotype similar to chronic lymphocytic leukemia, and dissecting signaling pathways at the pre-B stage, where disregulation can lead to B-precursor acute lymphocytic leukemia, will likely lead to important insights in designing rational therapies of these diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-K (02))
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Nasseri, M Faraz
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Research Institute of Fox Chase Cancer Center
United States
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