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.

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Myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) represent an overlapping spectrum of clonal preleukaemic conditions in which mutations have resulted in dysregulation of multipotent haemopoietic progenitors. An interstitial deletion of the long arm of chromosome 20 is a recurring abnormality associated with both of these classes of disorders. The association of 20q deletions with 'stem cell' disorders suggests that the deletion may mark the site of one or more genes, loss or inactivation of which perturbs the regulation of haemopoietic progenitors. The identification and study of the target gene(s) on chromosome 20q is therefore likely to illuminate the regulation of normal haemopoietic differentiation as well as the genesis of clonal myeloid disorders. This article provides a review of progress in the search for critical genes harboured within 20q deletions, together with a summary of several insights that these studies have provided into the biology of MPD and MDS.

Polycythemia vera (PV) is an acquired clonal disorder characterized by increased production of mature red cells and growth of erythroid colonies in the absence of erythropoietin. Mutation of the erythropoietin receptor has been demonstrated to cause familial polycythemia, but no mutations have been found in PV. Moreover, both erythroid and myeloid progenitors from patients with PV have been reported to be hypersensitive to a number of dierent growth factors. Attention has therefore focused on post-receptor signal transduction pathways. The SHP-1 gene is an especially attractive candidate gene. Firstly, SHP-1 binds to and negatively regulates signalling from the erythropoietin receptor and is likely to regulate other cytokine receptors in a similar manner. Secondly, absence of SHP-1 protein in the motheaten mouse is accompanied by increased sensitivity of hematopoietic progenitors to a number of cytokines including erythropoietin. Thirdly, familial or sporadic polycythemia in man may result from mutations of the SHP-1 binding domain of the erythropoietin receptor. We have therefore searched for mutations of the SHP-1 gene in genomic DNA from patients with PV. In this disease the majority of peripheral blood lymphocytes are not part of the malignant clone and a variable proportion of myeloid cells may arise from normal progenitors. We have therefore chosen to study DNA from puri®ed peripheral blood granulocytes obtained from nine women in whom the granulocytes were clonally derived. Southern analysis was used to show that the gene was not rearranged and densitometry con®rmed the presence of two copies of the gene in each DNA sample. Sequencing of the entire coding region and all splice junctions revealed no mutations. Hematopoietic transcription factor binding sites in the SHP-1 promoter region were intact and the methylation status of the two SHP-1 promoters in PV patients was identical to that in three normal controls. Finally, we showed that levels of SHP-1 protein in granulocytes from patients was similar to those from normal controls. These results demonstrate that the SHP-1 gene is structurally and transcriptionally intact in patients with PV.