Blood Spotlight From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms

Our knowledge of the genetic basis of these disorders began in 2005, when a unique base substitution in JAK2, the gene encoding Janus kinase 2,was found inpatientswith polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The background of our investigations was the previous finding that copy-neutral loss of heterozygosity of chromosome 9p (9pLOH) is the most common chromosomal abnormality in polycythemia vera: JAK2 maps on chromosome 9p24, inside the minimal 9pLOH region. Using a quantitative polymerase chain reaction–based allelic discrimination assay with a sensitivity of less than 1%, JAK2 (V617F) can be detected in about in 95% of patients with polycythemia vera and in 60% to 65% of those with essential thrombocythemia or primarymyelofibrosis (Table 1). The remaining 5%of patients with polycythemia vera carry a somatic mutation of JAK2 exon 12. Their hematologic phenotype is mainly an isolated erythrocytosis, but their outcomes are similar to those of patients with JAK2 (V617F). Therefore, polycythemia vera is a condition almost exclusively associated with gain-of-function mutations of JAK2. The genetic basis of the myeloproliferative neoplasms defined as essential thrombocythemia or primary myelofibrosis is more heterogeneous. Soon after the discovery of JAK2 (V617F), Pikman et al identified MPL (W515L) as a novel somatic activating mutation in myelofibrosis. Subsequent studies showed that somatic mutations of MPL exon 10 (mainly involving codon W515) are found in about 5% of patients with essential thrombocythemia or primary myelofibrosis.