Myeloproliferative neoplasm (polycythaemia vera [PV], essential thrombocytosis [ET], progressive myelofibrosis [PMF]) are a group of diseases that are characterised by increased proliferation of blood cells, splenomegaly, myelofibrosis, thrombosis and risk of malignant transformation. The year 2005 was a landmark year for myeloproliferative diseases. Four groups of scientists identified the presence of JAK2V617F mutations in PV. This mutation is present in about 98% patients with PV. Mutations of exon 12 of the JAK2 gene can be found in 1-2% of the PV. These patients do not show the JAK2V617F mutation. The discovery of these mutations gave a genetic definition PV making diagnosis objective.
PV is diagnosed by the presence primary erythrocytosis in the precession of a JAK2 mutation referred to above. Chronic myeloid leukaemia is diagnosed by demonstrating the BCR-ABL1 translocation. JAK2V617F is also present in 50-60% of ET and PMF. Mutation of the gene MPL is found in 1-2% patients of ET and 5-10% of the patients with PMF. The presence of these mutation helps make diagnosis. However, The diagnosis of PMF and ET in a large proportion of patients requires exclusion of a reactive disorder and other myeloproliferative diseases because these patients (38-49% of ET and 30-45% of PMF) have no genetic marker.
Two publications have shown that a large proportion of the patients with ET and PMF who do not have JAK have mutation calreticulin (CALR) (N Engl J Med. 2013;369(25):2391-2405, N Engl J Med. 2013;369(25):2379-2390). In addition to ET and PMF CALR mutations are found in the MDS/MPN overlap disorder and refractory anemia with ring sideroblasts with thrombocytosis (RARS-T). They are rare or absent in other myeloid or lymphoid neoplasms or solid tumors.
Calreticulin (CALR) is a major calcium binding protein. The gene for calreticulin is located on 19p13.2. About a quarter of ET and MF have mutation in the CALR gene. All CALR mutations are localised to exon 9 and generate a 1bp frameshift. As a result of this most or almost all the C terminal negative amino acids and calcium binding sites are lost. There is a complete loss of the KDEL endoplasmic reticulum binding sequence. These mutations have been identified in the haemopoietic stem cell and progenitor compartments. CALR mutations and JAK2 mutations are mutually exclusive.
CALR mutated myeloproliferative disease have a distinct clinical profile. These patients have a lower haemoglobin, lower leukocyte count, higher platelet count and a lower risk of thrombosis. Patients of PMF carrying a CALR mutation have a longer survival than those carrying JAK2 or MPL mutations. Patients with ET carrying the CALR mutations have a longer survival than those carrying the JALK2 mutation. There is no difference between the survival of ET patients carrying CALR mutations and MPL mutations.
Mutated CALR appears to stimulate STAT pathway. It appears to physically bind with the thrombopoietin receptor to stimulate STAT. The erythropoietin receptor is not needed for this action (Blood. 2015;10.1182/blood-2015-11-681932, Blood. 2015;126:LBA-4).