Involvement of chromosomes 9 and 11 in familial and sporadic polycythemia vera

Abstract

Polycythemia vera (PV) is an acquired clonal myeloproliferative disorder. Although the vast majority of PV cases are sporadic, few familial cases have been reported. We identified six families with multiple members with PV all having clonal myelopoiesis. The predisposition to PV follows an autosomal dominant trait with incomplete penetrance. Based on the clonality and genetic studies of these PV families, we propose a model of the PV pathogenesis according to which loss of heterozygosity (LOH) in the PV locus is the disease-initiating event. We excluded the linkage between the PV phenotype and markers on 20q (del20q is the most common cytogenetic lesion found in ∼8% of PV cases), the SHP-1 gene locus, and the c-mpl gene. Since none of the familial PV subjects had cytogenetic abnormalities that would identify regions with possible LOH, we performed a genome-wide screening for LOH by microsatellite PCR at 10 cM resolution in one of the familial PV subjects. We identified two loci with LOH one on chromosome 9p and the other on chromosome 11q. We examined 10 sporadic PV subjects for the presence of both of these defects. The 9p LOH was present in 3/10 (33%) of sporadic and 2/15 (13%) familial PV cases. We mapped the common LOH region on 9p to be located between D9S1813-D9S1833 that spans 37 cM. In all examined 9pLOH+ PV subjects, the 9pLOH was present in 100% of the EPO-independent colonies suggesting the 9pLOH was present in 100% of the EPO-independent colonies suggesting the 9pLOH might be the primary PV lesion or a secondary lesion providing clonal advantage to the PV clone. Mitotic recombination is the most frequent cause of LOH in both loci (LOH remains undetectable by cytogenetic analysis). The 11q LOH was present in 2/15 (13%) familial PV cases. The 11q LOH spans a 70 cM region between markers D11S2002-11qTER. The linkage analysis of both regions (that would eliminate secondary loci and further map the primary PV locus) is in progress.