JAK2V617F/TET2 mutations: does the order matter?

According to the World Health Organization classification, myeloproliferative neoplasms (MPN) include chronic myelogenous leukemia, also known as BCR-ABL1–positive MPN, classic BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and non-classic forms (i.e. systemic mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia and unclassifiable MPN). All these subtypes are stem cell-derived clonal myeloproliferation, associated with the overproduction of mature blood elements and variable rates of transformation to acute myeloid leukemia (AML).1 JAK2V617F activating mutation is the most prevalent abnormality observed in BCR-ABL1-negative MPN, found in virtually all cases of PV and in about half of ET and PMF (96%, 55% and 65%, respectively). This mutation lies in the pseudokinase-domain of JAK2 and disrupts its regulatory activity. Another mutation affecting JAK2 exon 12 is observed in 3% of all PV cases. Mutations affecting W515 of the thrombopoietin receptor MPL are detected in PMF and ET patients. Additional mutations have been identified in MPN (reviewed in 1). Defects in the control of intracellular signaling involve mutations in LNK and CBL genes. Genetic abnormalities affecting epigenetic regulation, and possibly responsible for disease initiation, concern the ASXL1, EZH2 and TET2 genes. Finally, mutation in IKZF1 and IDH1/2 may be implicated in MPN transformation. In PV, among these additional mutations to JAK2V617F, TET2 mutations are those most frequently reported (16%); the others are only described in small subsets of patients.1 TET2 belongs to a family of three conserved genes in mammals: TET1, TET2 and TET3. The founding member of the family, TET1, has been identified as a fusion partner of MLL in the t(10;11)(q22;q23) translocation of acute leukemia.2,3 The involvement of TET3 in hematologic disorder has not yet been described. The TET proteins are members of the 2-oxoglutarate (2-OG)- and Fe(II)-dependent dioxygenase that are able to convert 5-methyl-cytosine (5-mC) to 5-hydroxymethylcytosine (hmC).4,5 Recent reports indicate an important role for TET1 and TET2 (and, therefore, hmC) in the control of ES cell self-renewal and differentiation.6 TET3 might be involved in genome reprogramming following fecundation.7