This grant over the past 24 years has supported a wide range of studies focused broadly on immunoglobulin gene expression. This renewal concentrates on the forkhead transcription factor, Foxp1. Conventional Foxp1 knockout (KO) leads to mid-gestation cardiovascular dysfunction and lethality. RAG2-/- reconstitution studies demonstrated an intrinsic block of B cell development at the pro-B stage. Thymic development in Foxp1-/--reconstituted RAG-/- mice is normal, but peripheral CD4 T cell subsets and functions are deregulated. We propose to generation conditional Foxp1 knockout mice to study the effects of intrinsic Foxp1 deficiency on B cell and T cell development. We propose to identify Foxp1 target genes to define pathways and mechanisms by which Foxp1 contributes to normal and malignant B cell development. These studies hold clinical relevance in that Foxp1 over- expression is a hallmark of the most aggressive and worst prognostic subset of diffuse large B cell lymphoma. Philip W. Cancer is often caused by abnormal expression of transcription factors, which regulate the expression of many additional genes. Diffuse large B cell lymphoma (DLBCL) accounts for ~40% of cancers of white blood cells. The transcription factor, Foxp1, is abnormally high in the most aggressive form of DLBCL and has been termed a """"""""signature gene"""""""" of this malignancy. By understanding more about Foxp1 and the genes deregulated by its over-expression, we can better understand basic mechanisms underlying DLBCL. PHS 398/2590
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