Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers that involve the overproduction of blood cells in the bone marrow. In MPNs, the bone marrow produces too many red blood cells, white blood cells, or platelets, leading to various health problems. There are several types of MPNs, including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Majority of MPNs comprise of mutations in one of the three genes JAK2, MPL and CALR, and their presence can be used to identify and characterize MPNs.

The JAK2 (Janus kinase 2) gene encodes for a non-receptor protein tyrosine kinase that activates cytokine and growth factor signaling. The V617F mutation results in constitutive activation of JAK2 and downstream STAT5 and ERK signaling. This mutation is mainly observed in PV, ET and PMF. It is also infrequently present in myelodysplastic syndrome, chronic myelomonocytic leukemia and other atypical chronic myeloid disorders. A small percentage of JAK2 mutation positive patients contain other non-V617F mutations within exons 12 to 15. In particular, mutations in exon 12 of JAK2 have been observed in patients with PV.

The CALR (Calreticulin) gene encodes for a multifunctional calcium-binding protein involved in many cellular activities such as growth, proliferation, adhesion and programmed cell death. CALR mutations are found in patients with JAK2-negative essential thrombocythemia (ET) and JAK2-negative primary myelofibrosis(PMF). Only a minority of patients with myelodysplasia have mutations in the CALR gene.

The MPL (myeloproliferative leukemia virus oncogene) gene encodes the thrombopoietin receptor, which regulates hematopoiesis and megakaryopoiesis. Activating MPL mutations are associated with a subset of myeloproliferative neoplasms and acute megakaryoblastic leukemia. MPL W515 mutations are present patients with primary myelofibrosis (PMF) and essential thrombocythemia (ET). The S505 mutation is detected in patients with hereditary thrombocythemia.

Testing for these mutations is crucial for diagnosing specific subtypes of MPNs and determining the most appropriate treatment and management strategies for patients.