Hematopoietic Stem Cell Kinetics, Control Of

Hematopoietic stem cells (HSCs) are primitive and generally quiescent cells that are able to support multilineage hematopoiesis. The large numbers of HSCs and redundancy in cytokine function and signal transduction mechanisms assure a stable production of blood cells throughout life. Females are natural mosaics for X chromosome-linked genes. Since X-chromosome inactivation occurs randomly, the ratio of parental phenotypes among blood cells is approximately 1 to 1. Approximately 50% of blood cells from neonates and females less than 40 years of age express maternal X chromosome genes, and 50% express paternal X chromosome genes. However, excessive skewing, defined as parental phenotype ratios greater than 3 to 1, occurs in 38 to 56% of normal females over 60 years of age (Busque et al., 1996; Gale et al., 1997; Champion et al., 1997). This has been attributed to the depletion of HSCs with aging (and the support of blood cell production by the few remaining clones) or to myelodysplasia (the dominance of a neoplastic clone). Each possibility has major implications for chemotherapy and for transplantation in elderly patients. Another possibility is hemizygous selection (a competitive advantage of all cells that express 1 parental phenotype), which is difficult to exclude in studies in an outbred human population. Abkowitz et al. (1998) found similar findings of excess skewing in longitudinal studies of female Safari cats and demonstrated that the excessive skewing has no pathologic consequence and results from hemizygous selection. Safari cats are the F1 offspring of Geoffroy (G) and domestic (d) cat parents. Abkowitz et al. (1998) showed a competitive advantage for all HSCs with a specific X chromosome phenotype and thus demonstrated that an X chromosome gene (or genes) regulates HSC replication, differentiation, and/or survival. Because of X chromosome inactivation early in embryogenesis, each somatic cell in female Safari cats, including each stem cell, expresses a d or G form of glucose-6-phosphate dehydrogenase (G6PD; 305900) but not both. Each progenitor and differentiated cell expresses the G6PD phenotype of the HSC from which it derived.

There are many examples of hemizygous selection of differentiating blood cells in the human: in platelets and T cells of women heterozygous for the Wiskott-Aldrich syndrome (301000), in B cells of women heterozygous for agammaglobulinemia (300755), and so on. The identity of the gene or genes responsible for the selective growth advantage of HSCs with the G type of G6PD is unknown. Because Geoffroy cats (of South American origin) and domestic cats (of Eurasian origin) have evolved independently for 12 million years, it is likely that F1 Safari cats will be heterozygous at many genetic loci. Candidate genes include the cell cycle relevant determinants (300023) on Xq28 and the inhibitor of apoptosis gene (300079) on Xq25. Another candidate is the PIGA gene (311770) on Xp22.1, which is responsible for paroxysmal nocturnal hemoglobinuria (300818). Luzzatto et al. (1979) found a suggestion of hemizygous expansion of HSCs in studying heterozygotes for the Ilesha variant of G6PD in a Nigerian family with no coexistent X-chromosome-linked clinical disorder. As only red cells and granulocytes were studied, however, their observations were also compatible with a preferential (nonrandom) inactivation of the X chromosome, rather than selection with aging. Recombination between the loci for G6PD and that for hemizygous selection occurred in 3 of 5 individuals in this family.

Henckaerts et al. (2002) stated that in as many as 50% of elderly women, progressive skewing of X inactivation occurs in the hematopoietic system (Champion et al., 1997; Christensen et al., 2000). Similar data were obtained in cats, in which skewed X-chromosome inactivation in all hematopoietic lineages also occurred after bone marrow transplantation (Abkowitz et al., 1998) and after repeated chemotherapy with busulfan (Abkowitz et al. (1988, 1993)). Human female monozygotic twins that show skewed X inactivation in the hematopoietic system with aging tend to inactivate the X chromosome from the same parent (Christensen et al., 2000; Vickers et al., 2001). Thus, alleles on the X chromosome confer a growth, survival, or reconstitution advantage to stem cells. Progressive skewing of X inactivation in the hematopoietic system is likely to be caused, to a large extent, by hemizygous selection, i.e., a selective advantage of one X chromosome over another, whereas stochastic mechanisms are less dominant.