GENETIC REGULATION OF HEMATOPOIESIS

Stanford University, Stanford CA

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Abstract

A central issue in hematopoietic stem cell biology is to understand the mechanisms that regulate self-renewal, which is required for hematopoiesis to persist for the lifetime of the animal. A cDNA library was constructed from pure populations of hematopoietic stem cells with self-renewal capacity and used to analyze genes that were differentially by this population and pluripotent hematopoietic progenitor cells without self-renewal capacity. This approach has led to the identification of genes that regulate stem cell self renewal, hematopoietic cell homing, as well as several candidate genes that may also be involved in stem cell fate decisions. We found that the HSCs expressed the bmi1 oncogene, which is a Polycomb-group gene that represses expression of Hox genes during development, and regulates cell proliferation and senescence by down-regulating the ink4a locus. The ink4a locus expresses two genes by alternative splicing: p16 is a G1 cyclin inhibitor and p19/ARF stabilizes expression of p53 by binding to Mdm2. We thus examined the HSC compartment in bmi1-deficient ("knockout" or "KO") mice and found that such mice had normal numbers of fetal liver HSCs. However, these mice displayed a 4-8-fold reduction in adult HSCs. The aims of this renewal are to extend these findings and to gain further insights into the regulation of stem cell functions, particularly self-renewal, via the following aims. Specific Aim #1: To define the mechanism by which bmi1 affects hematopoietic stem cell fate. Specific Aim #2: To define the gene expression profile of bmi1 deficient hematopoietic stem cells. Specific Aim #3: To use bioinformatics to analyze the pathways altered by the absence of expression of bmi1 in hematopoietic stem cells. Specific Aim #4: Analysis of other candidate stem cell regulatory genes identified in our genomics analysis.