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Chapter 068. Hematopoietic Stem Cells (Part 5)

Some limited understanding of self-renewal exists and, intriguingly, implicates gene products that are associated with the chromatin state, a high-order organization of chromosomal DNA that influences transcription. These include members of the polycomb family, a group of zinc finger–containing transcriptional regulators that interact with the chromatin structure, contributing to the accessibility of groups of genes for transcription. Certain members, including Bmi-1 and Gfi-1, are important in enabling hematopoietic stem cell self-renewal through modification of cell cycle regulators such as the cyclin-dependent kinase inhibitors. In the absence of either of these genes, hematopoietic stem cells decline in number and function | Chapter 068. Hematopoietic Stem Cells Part 5 Some limited understanding of self-renewal exists and intriguingly implicates gene products that are associated with the chromatin state a high-order organization of chromosomal DNA that influences transcription. These include members of the polycomb family a group of zinc finger-containing transcriptional regulators that interact with the chromatin structure contributing to the accessibility of groups of genes for transcription. Certain members including Bmi-1 and Gfi-1 are important in enabling hematopoietic stem cell self-renewal through modification of cell cycle regulators such as the cyclin-dependent kinase inhibitors. In the absence of either of these genes hematopoietic stem cells decline in number and function. In contrast dysregulation of Bmi-1 has been associated with leukemia it may promote leukemic stem cell self-renewal when it is overexpressed. Other transcription regulators have also been associated with selfrenewal particularly homeobox or hox genes. These transcription factors are named for their ability to govern large numbers of genes including those determining body patterning in invertebrates. HoxB4 is capable of inducing extensive self-renewal of stem cells through its DNA-binding motif. Other members of the hox family of genes have been noted to affect normal stem cells but they are also associated with leukemia. External signals that may influence the relative self-renewal versus differentiation outcomes of stem cell cycling include the Notch ligands and specific Wnt ligands. Intracellular signal transducing intermediates are also implicated in regulating self-renewal but interestingly are not usually associated with the pathways activated by Notch or Wnt receptors. They include PTEN an inhibitor of the AKT pathway and STAT5 both of which are usually downstream of activated growth factor receptors and necessary for normal stem cell functions including self-renewal at least in mouse models. The .