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Forum on Microbial Threats

Mutations restricted to MPNs and their role in the MPN pathogenesis

JAK2 gene mutations

Before 2005, the molecular pathogenesis of the BCR-ABL1 classical MPNs was unknown. In 2005, a major breakthrough was the discovery of a G to T somatic mutation at nucleotide 1849, in exon 14 of JAK2, resulting in the substitution of valine to phenylalanine at codon 617 (JAK2V617F) in the pseudokinase domain.47This mutation can be found in around 70% of MPNs: 95% of PV and 50% to 60% of ET and PMF. The JAK2V617F mutation often undergoes a transition from heterozygosity to homozygosity due to occurrence of mitotic recombination resulting in copy-neutral loss of heterozygosity along a variable size region on the short arm of chromosome 9 (9pLOH).The JAK2V617F mutation arises in a multipotent hematopoietic progenitor, is present in all myeloid lineages, and can be also detected in lymphoid cells, mainly B and NK cells and more rarely and later in disease in T cells. It is absent in nonhematopoietic cells although it has been found in endothelial cells of the spleen and of splanchnic veins of patients with MF and/or splanchnic thrombosis as the Budd-Chiari syndrome.9 The variant allele frequency (VAF) in granulocytes is highly variable, with a continuum between the threshold of detection (around 1%) to 100%. The VAF is usually low in ET (around 25%), is higher in PV (frequently over 50%), and is close to 100% in post-PV or post-ET MF. In PMF, the VAF is variable, but frequently high