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Interstitial deletion constitutes the major mechanism for loss of
heterozygosity on chromosome 20q in polycythemia vera
FA Asimakopoulos, JG Gilbert, MA Aldred, TC Pearson and AR Green
Department of Haematology, University of Cambridge, UK.
An acquired deletion of the long arm of chromosome 20 is a recurrent
abnormality in myeloproliferative disorders, particularly polycythemia vera
and myelodysplastic syndromes. The association of 20q deletions with
myeloid "stem cell" disorders suggests that the deletions mark the site of
one or more genes, loss or inactivation of which plays a role in the
regulation of normal hematopoietic progenitors. We have recently performed
a detailed molecular analysis of 20q deletions in peripheral blood (PB)
granulocytes and defined a commonly deleted region of 16 to 21 centimorgan
(cM). To further reduce the size of the common deleted region we have
searched for small deletions or mitotic recombination events, neither of
which would be detected by conventional cytogenetics. We have studied 48
patients with polycythemia vera and four patients with idiopathic
myelofibrosis. In each case, cytogenetic analysis had either failed or had
shown no abnormalities of chromosome 20. Seventeen microsatellite markers
that span the common deleted region were used to search for loss of
heterozygosity in granulocyte DNA. No instance of microsatellite
instability was observed in a total of 880 comparisons of granulocyte and
T-cell DNA. Granulocyte DNA from four patients exhibited allele loss on
20q. In each case the allele loss was caused by an interstitial deletion
because heterozygosity at distal markers was retained and because
quantitative Southern blotting demonstrated hemizygosity. Loss of
heterozygosity in PB granulocytes would be masked by the presence of
significant numbers of normal granulocytes not derived from the malignant
clone. Therefore, the human androgen receptor assay (HUMARA) was used to
determine granulocyte clonality. In 21 of 27 informative female patients
the majority of the granulocytes were clonally derived. In 5 patients the
granulocytes appeared polyclonal and in 1 patient unilateral X inactivation
was observed in both granulocytes and T cells. These results show that, in
the vast majority of patients presented here, the failure to detect loss of
heterozygosity cannot be attributed to the presence of normal polyclonal
granulocytes. Our results therefore show that allele loss on chromosome 20q
in polycythemia vera does not commonly involve mitotic recombination or
chromosome loss and that microsatellite instability is a rare event in this
disorder.
Volume 88,
Issue 7,
pp. 2690-2698,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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