Validation of two novel mouse models of conditional Meis1 deletion to study roles in adult mouse hematopoiesis

Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox¬ transcription factor co-factor and independently. Despite the emerging recognition of Meis1’s importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1’s functions and the relevant pathways and genes mediating its functions. In this thesis, I provide the groundwork for a novel model system to explore Meis1 function. Mice with a loxP flanked Meis1 allele were crossed with two different conditional Cre-recombinase expressing strains, MxCre mouse and the ERTCre mouse. I validated conditional deletion of the Meis1 allele and the resultant decrease in mRNA and protein expression. I additionally studied expression of Meis1 related (MEINOX family) transcription factors in highly purified hematopoietic populations to generate an atlas of gene expression and focus our future studies. The inducible Meis1-deletion mice were then used to study if Meis1 is a requirement to maintain hematopoietic homeostasis in adult mice. I provide evidence for a critical role for Meis1 in hematopoietic stem cell maintenance and megakaryocytic and erythroid progenitor expansion in vivo. I furthermore identified two novel candidate effectors of Meis1 in the adult hematopoietic system, Hlf and Msi2 using Affymetrix expression analysis. As recent studies have suggested a role for Meis1 in the regulation of hypoxia-induced reactive oxygen species (ROS), I examined the impact of the ROS-scavenger N-acetyl-L-cysteine on the Meis1-/- phenotype in vivo. The results highlighted in this thesis provide direction and an experimental platform for further dissection of the mechanisms of Meis1 function in both normal and leukemic hematopoiesis.Medicine, Faculty ofMedical Genetics, Department ofGraduat