High Frequency of Loss of Heterozygosity and Chromosomal Imbalances in Patients with Myelofibrosis

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder belonging to the non-chronic-myeloid-leukemia myeloproliferative neoplasms. Cardinal features of myelofibrosis include extramedullary hematopoiesis, hepatosplenomegaly and cytopenias. The disease can occur de novo as primary MF or result from the progression of polycythemia vera or essential thrombocythemia with no differences in clinical or histological characteristics. Though several large chromosome abnormalities have been described in patients with myelofibrosis there are no previous studies screening for both CNVs and LOH (loss of heterozygosity) in patients with MF. We studied 11 patients using CytoScan platform (750k or HD- Affymetrix). This platform allows the identification of copy number variations as well as segments of loss of heterozygosity. Forty-five percent (5/11) presented pathogenic/possibly pathogenic CNVs and 72% (8/11) presented large segments of loss of heterozygosity (>10Mb). Two patients had a single CNV without any LOH. Two patients had a single LOH. All others have multiple LOH with (3) or without (4) CNVs. The most frequent abnormality was LOH of 9p (3/11) and deletion 13q (2/11). All other alterations were non-recurrent. One patient had a small deletion including exons 1 and 2 of NOTCH2, a gene known to be involved in hematological malignancies. The most frequent abnormality reported in the literature is 20q deletion. In our cohort only one patient had the 20q deletion and also had multiple complex chromosome rearrangements on chromosomes 7 and 12 and a large LOH on chromosome 3p. The study shows that CNV and LOH are frequent and may be involved in pathogenesis of the disease. However, the role of these changes in the pathogenesis are not yet clear.