Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes

Abstract

Summary. Studies of X chromosome inactivation patterns are central to many aspects of our understanding of the pathogenesis of haematological malignancies. In patients with myeloproliferative disorders and myelodysplastic syndromes the demonstration of skewed X inactivation patterns in multiple haemopoietic lineages has been taken to indicate a stem cell origin for these groups of diseases. However, stem cell depletion or selection pressures can also produce skewed X inactivation patterns and might increase with age. We have therefore used the HUMARA assay to study X inactivation patterns of elderly patients with myeloproliferative disorders together with an age-matched control group of normal elderly women.A clonal pattern (clonal granulocytes and polyclonal T cells) was observed in 23 . 1% of normal women and 63 . 4% of patients with myeloproliferative disorders. This is the first report of X inactivation patterns in purified subpopulations of blood cells in normal elderly women. These results have three significant implications. Firstly, the finding of clonal granulocytes and polyclonal T cells in normal elderly women is likely to reflect age-related stem cell depletion or selection pressures. Secondly, the demonstration of clonal granulocytes and polyclonal T cells is not a useful diagnostic marker for myeloproliferative disorders or myelodysplastic syndromes in elderly women. Thirdly, our data raise the possibility that clonal blood cell patterns may precede rather than follow mutations which subsequently give rise to myelodysplastic or myeloproliferative phenotypes.

A Novel, Essential Control for Clonality Analysis with Human Androgen Receptor Gene Polymerase Chain Reaction

“…26 Excessively skewed XCIPs are also found in hematopoietic cells of healthy elderly females (ϳ40% of individuals older than 60 years of age). [27][28][29] This acquired skewing is mainly because of selective pressure for one or more genetic differences between the two X-chromosomes. 30 -32 Apart from false clonality, false polyclonality may be observed.…”

X-inactivation analysis in the 1990s: promise and potential problems

“…These results have subsequently been confirmed by other investigators. [40][41][42] Since the incidence of skewing may vary more than fourfold depending on the age of the population, it is clear that the age of the cohort analyzed may constitute the major confounding factor explaining the discrepancy of previous studies.…”

Acquired skewing of Lyonization remains stable for a prolonged period in healthy blood donors

“…Alternatively, polymorphisms in genes located on the X-chromosome may lead to selection of cells with one particular active X-chromosome and to a skewed XCIP. 7,8 Such polymorphisms should be present in genes regulating the decision of self-renewal or differentiation after stem cell division, or in genes affecting growth rate or survival of cells. Abkowitz et al 19 have shown in cats that acquired skewing of XCIP is likely to be caused by a polymorphic gene on the X-chromosome.…”

“…However, several reports have shown an increase in the number of females with a skewed XCIP in blood leukocytes with increasing age. [7][8][9][10][11] The percentage of females with a ratio of more than 75% of either allele in granulocytes may be as high as 40% after the age of 65. The skewing in T cells seems to lag behind, which may give rise to a different XCIP for T cells and granulocytes.…”