Genetic Basis of Polycythemia Vera

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Polycythemia vera (PV) is the most common myeloproliferative disorder. Relevance of this project to the public health is that elucidation of molecular PV defect will result in specific therapy and eventual cure of PV. Based on our previous studies, we hypothesize that PV is caused by changes in gene expression at several levels. Identification of our finding of the chromosome 9p uniparenteral disomy was reproduced and provided the basis for the recent discovery of the constitutively active mutant JAK2 V617F on chromosome 9p that is present in the majority of PV patients: JAK2 is mutated in a single allele and it is converted to homozygosity by uniparenteral disomy in approximately 30% of PV patients. However, the JAK2 V617F alteration does not fully explain the pathophysiology of PV. 1) We hypothesize that other genetic events are needed for the development of the full PV phenotype. In these studies we will pursue a) identification of positional candidates through familial co-segregation of genomic regions with the PV phenotype. b) identification of positional candidates by shared regions of genome architecture or expression changes, c) we will guide our genomic analyses by using the fund of knowledge about JAK2, its pathways and interacting proteins, and analyzing those PV patients without JAK2 V617F mutation. 2) a) We will study the cellular and biochemical effect of JAK2 V617F in cell lines and correlate these with the effect of tyrosine kinase inhibitors; similar studies will be done in polycythemic mice with JAK2 V617F in hematopoietic cells, b) We will correlate the PV clinical response (an ongoing clinical study of imatinib mesylate with Dr. Verstorvsek - see project 6) to imatinib mesylate with their JAK2 V617F genotype and expression, c) We will attempt to identify the pathophysiology of PV in those patients who respond to imatinib mesylate.