The blood forming system of vertebrates develops during embryogenesis in several spatio-temporal waves that produce specialized cell types suited for the needs of the embryo. From cells generated in the embryo, adult hematopoietic stem cells (HSCs) form. Adult HSCs, in turn, continue to replenish themselves and yield progeny that populate most blood lineages in the adult. Understanding the processes and molecules controlling and responding to these transitions underlies our ability to manipulate normal and aberrant hematopoiesis for purposes such as stem cell therapy. In this proposal, we will use a murine loss-of-function model in the MII gene to probe early embryonic stages of blood development as well as steady-state hematopoiesis in the adult. The MII gene is a proto-oncogene that participates in the developmental regulation of Hox and other target genes by modifying chromatin. We have shown that MII is required for the development of definitive hematopoietic lineages. Here, we seek to provide detailed information regarding the developmental dynamics and mechanism by which MII participates in the development of hematopoietic lineages. Specifically, we will 1) identify MLL-dependent processes during embryonic HSC specification and expansion by transplanting hematopoietic tissues from MII mutant embryos into appropriate recipients, 2) exploit an in vitro system to identify and manipulate MLL target genes that are important for promoting blood development, and 3) use conditional inactivation of the MII locus in adult steady-state hematopoietic populations to identify and study MII-dependent processes during and beyond lineage commitment. The goal of this proposal is to uncover important regulatory processes and networks in the development and maintenance of the hematopoetic system using a gene known to be critical for these processes. This award will provide a period of mentorship for Dr. Patricia Ernst, the principal investigator, with Dr. Stanley Korsmeyer, the sponsor. Dr. Ernst has established the systems to carry out this proposal in the sponsor's laboratory. Dr. Korsmyeyer is a world leader in the field of oncogenesis establishing the importance of apoptosis in this process. Dr. Korsmeyer has a strong record of training and fostering independent investigators

K01DK067119

2004-04-10

2010-03-31