Abstract
We applied single nucleotide polymorphism arrays (SNP-A) to study karyotypic abnormalities in patients with atypical myeloproliferative syndromes (MPD), including myeloproliferative/myelodysplastic syndrome overlap both positive and negative for the JAK2 V617F mutation and secondary acute myeloid leukemia (AML). In typical MPD cases (N = 8), which served as a control group, those with a homozygous V617F mutation showed clear uniparental disomy (UPD) of 9p using SNP-A. Consistent with possible genomic instability, in 19/30 MDS/MPD-U patients, we found additional lesions not identified by metaphase cytogenetics. In addition to UPD9p, we also have detected UPD affecting other chromosomes, including 1 (2/30), 11 (4/30), 12 (1/30) and 22 (1/30). Transformation to AML was observed in 8/30 patients. In 5 V617F+ patients who progressed to AML, we show that SNP-A can allow for the detection of two modes of transformation: leukemic blasts evolving from either a wild-type jak2 precursor carrying other acquired chromosomal defects, or from a V617F+ mutant progenitor characterized by UPD9p. SNP-A-based detection of cryptic lesions in MDS/MPD-U may help explain the clinical heterogeneity of this disorder.
Highlights
Acquired loss of heterozygosity (LOH) can occur either as a result of deletions or mitotic recombination
Using 50K single nucleotide polymorphism arrays (SNP-A), we recently identified a high frequency of uniparental disomy (UPD) in myelodysplastic syndromes (MDS) as well, occurring in approximately 30% of patients [6]
To determine whether or not SNP-A can be used as an accurate and effective method to identify acquired UPD, we studied patients with typical myeloproliferative syndromes (MPD) homozygous for the V617F mutation
Summary
Acquired loss of heterozygosity (LOH) can occur either as a result of deletions or mitotic recombination (uniparental disomy [UPD]). LOH has been described in many malignant hematologic conditions including acute myelogenous leukemia (AML), as well as solid cancers [1,2,3,4,5]. Using 50K single nucleotide polymorphism arrays (SNP-A), we recently identified a high frequency of UPD in myelodysplastic syndromes (MDS) as well, occurring in approximately 30% of patients [6]. Other previously cryptic aberrations not detected by metaphase cytogenetics (MC) were identified in all sub-types of MDS, including secondary leukemias [6]. We have extensively validated this technology with regard to its sensitivity and resolution for detecting acquired loss of heterozygosity, gains, and micro-deletions [8]
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