ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human Mixed Lineage Leukemia (MLL) gene was originally isolated at the site of frequent chromosomal translocations in acute leukemia. MLL translocations are particularly associated with infant leukemia as well as secondary leukemias in adults. Such chromosomal translocations result in the expression of a fusion oncogene composed of the N-terminus of MLL fused to one of many identified fusion partners. To understand the mechanisms by which MLL fusion proteins are leukemogenic, it is critical to determine the normal function of MLL in vivo, particularly in the cell types that may represent the target for transformation by MLL oncogenes. We have previously demonstrated that murine Mll is essential for embryonic hematopoietic stem cell (HSC) development but its importance during adult hematopoiesis was unknown due to the embryonic lethality of homozygous Mll loss. Using an inducible knockout model we will determine the normal role of Mll in the hematopoietic system. These studies will identify roles for Mll in 1) HSC homeostasis within the bone marrow, 2) multipotent progenitor function and homeostasis, and 3) differentiating cell types using lineage-specific cre recombinase strains. Studies will include phenotypic and functional analysis of all hematopoietic stem and progenitor populations described above. A focus on the identification of target genes deregulated in absence of Mll will establish a set of candidate genes that are both potential direct targets and potentially responsible for the phenotypes discovered in the course of these studies. Future studies will assess whether these same target genes and pathways are perturbed by Mll fusion oncogenes.