Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) can be viewed as clonal premalignant disorders that precede development of acute leukemia wherein the order of mutation acquisition, together with environmental insults such as inflammation, matters. MPN disease-defining somatic mutations are in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL; a gene encoding thrombopoietin receptor) genes.
Several studies have revealed other somatic mutations affecting intracellular signaling of hematopoietic stem cells in MPNs, but these are considered as phenotype-modifying, not disease-initiating, mutations, such as Tet methylcytosine dioxygenase 2 (TET2) mutations, which may precede or follow acquisition of JAK2V617F. However, the order of TET2 mutation occurrence alters the transcriptional program in hematopoietic stem cells and patients' clinical outcome.
In polycythemia vera (PV), the JAK2V617F mutation is present in the vast majority of patients, yet is not always the disease-initiating mutation and constitutes only part of the clone. We reported in 2014 the mutational landscape of 31 JAK2V617F-positive PV patients and identified 2 patients with an acquired polycythemia phenotype carrying JAK2 variants at conserved residues of JAK2: first (T108A) in the 4-point, ezrin, radixin, moesin (FERM) domain, and the other (L393V) in 7 amino acids upstream of the Src homology 2 (SH2) domain.