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. My group aims to understand the normal function of the MLL proto-oncogene particularly during the development and function of the hematopoietic system. The MLL gene encodes a large nuclear chromatin regulator that is disrupted in common chromosomal translocations found in leukemia. To study the normal role of MLL during hematopoiesis, we have developed a loxP-flanked allele of the murine Mll gene, backcrossed this strain and crossed these animals to either inducible or lineage-specific Cre recombinase mouse strains. This approach allowed us to study the effect of Mll loss on multiple hematopoietic cell types during adult steady state hematopoiesis. Using this model, we demonstrated that the maintenance of hematopoietic stem and progenitor populations absolutely depends on Mll. We demonstrated that this was likely due to two different cell-context dependent roles of Mll in these primitive cell types. First, Mll deletion in hematopoietic stem cells resulted in their escape from quiescence and an increase in proliferation, coupled to symmetric differentiation of progeny cells. This resulted in the rapid exhaustion of stem cell activity from the bone marrow. Second, we demonstrated that in myelo-erythroid progenitors, Mll deficiency resulted in the reduction in proliferation resulting in reduced progenitor pool sizes. Together, these alterations resulted in the rapid decline in bone marrow cell numbers upon Mll deletion and ultimately bone marrow failure and animal death. Surprisingly, when we crossed the Mll loxP flanked strain to Cre transgenic animals that express Cre only in differentiating lineages (T cells [lck-Cre], B cells [CD19-Cre] or myelomonocytic precursors [lysozyme M-Cre]), we found that there was no effect on steady state cell numbers, demonstrating that Mll is only essential in the early stem and progenitor populations. In the current proposal, we focused on a potential independent MLL function in T cell activation, as we had demonstrated a biochemical collaboration between domains within MLL and the sequence-specific activator CREB, which is known to function in T cell activation.