Somatic mutations of calreticulin in myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms.

According to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myeloproliferative neoplasms (MPN) include chronic myeloid leukemia and the so-called Philadelphia-negative myeloproliferative neoplasms, i.e. essential thrombocythemia, polycythemia vera and primary myelofibrosis. Myeloproliferative features are also observed in a group of disorders classified as myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This category includes clonal myeloid neoplasms that at the time of initial presentation have some features that support a diagnosis of myelodysplastic syndrome (MDS), and other findings more consistent with MPN. MDS/MPN include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN, unclassifiable (MDS/MPN, U). Of these latter unclassifiable conditions, the best characterized is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T). The genetic basis of MPN and MDS/MPN has been broadly defined in the last ten years and is summarized in Table 1. The unique JAK2 (V617F) mutation is found not only in about 80% of all patients with a myeloproliferative neoplasm, but also in a fraction of patients with MDS/MPN, including CMML and RARS-T. In CMML, the mutation is detected in about 10% of cases and is significantly associated with myeloproliferative features, including high leukocyte and monocyte counts and splenomegaly. RARS-T is characterized by anemia with dysplastic, ineffective erythroid proliferation and bone marrow ring sideroblasts, associated with high platelet count and proliferation of large atypical megakaryocytes. JAK2 (V617F) is detectable in about 50%-60% of patients. Occasional patients with mutations in MPL or JAK2 exon12 have been reported. The analysis of the mutant allele burden suggests that the disease may result from a combination of SF3B1 mutation, which usually occurs as an early event and is responsible for myelodysplastic features and