Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders

Abstract

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n ‫؍‬ 28), chronic or acute myeloid leukemia (n ‫؍‬ 35), secondary erythrocytosis (n ‫؍‬ 4), or healthy controls (n ‫؍‬ 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. IntroductionChronic myeloproliferative diseases (CMPDs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages in the bone marrow and increased numbers of mature and immature cells in the peripheral blood. CMPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes such as chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), and chronic eosinophilic leukemia (CEL). These diseases overlap with myelodysplastic/myeloproliferative diseases (MDS/MPDs) such as atypical CML (aCML) and chronic myelomonocytic leukemia (CMML), in which proliferation is accompanied by dysplastic features or ineffective hematopoiesis in other lineages. 1 We refer here broadly to all these groups as myeloproliferative disorders (MPDs).Although there are strict diagnostic criteria for MPD subtypes, precise categorization remains a subject of debate 2 and furthermore, it can be difficult to differentiate some cases from reactive disorders. Only CML is characterized by a pathognomonic molecular marker, the BCR-ABL fusion, and the primary abnormalities driving excess proliferation in most other cases have been obscure. However, several lines of evidence have implicated aberrant tyrosine kinase signaling as the root cause of MPDs. Breakpoint cluster region-abelson (BCR-ABL) itself is a constitutively active tyrosine kinase that is believed to be the primary, and probably the only, driving force behind chronic-phase CML. 3 Other gene fusions have been identified in rare cases of aCML, CMML, and HES/CEL that involve the tyrosine kinases PDGFRA, PDGFRB, FGFR1, and JAK2. 4,5 In addition, the KIT receptor is activated by point mutation in the majority...

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

“…This frequency of JAK2 V617F positivity in splenic EMH cases is similar to those previously reported using peripheral blood and bone marrow samples from patients with PV, CIMF and ET. [6][7][8][9]12,13,[25][26][27] These findings confirm that JAK2 V617F is predominantly associated with the hematopoiesis of non-CML CMPD clones, even in the setting of splenic EMH. Of interest, although our sample size was relatively small, the frequency of JAK2 V617F in splenic EMH cases associated with MDS and CMML appears to be slightly higher than those previously described in peripheral blood or bone marrow studies.…”

“…The JAK2 V617F allele, present in all hematopoietic cells arising from the neoplastic clone, has been detected in the majority of cases of polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (CIMF) and acute leukemia transformed from a preexisting CMPD, but it is rarely identified in healthy controls or patients with other myeloid disorders. [6][7][8][9][10][11][12][13] Functioning as a constitutively activated cytoplasmic tyrosine kinase, the mutated JAK2 V617F protein probably mediates myeoloproliferation via dysregulation of various JAK2/STAT5 signaling pathways. Targeted genes, including the antiapoptotic protein Bcl-xL, have been implicated in vital cellular processes such as proliferation and survival.…”

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

“…However, PV, IMF and ET have more in common phenotypically with each other than with these other disorders and this was confirmed genotypically by the discovery of the JAK2 V617F mutation(6), the expression of which is largely confined to PV, IMF and ET (19).…”

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

“…Cytokine receptors for erythropoietin, thrombopoietin, and CSF3 lack phosphorylation activity and upon activation by their respective ligand binding induce phosphorylation of JAKs, which then phosphorylate further downstream targets regulating transcription such as the STAT pathway [50]. The somatic JAK2-V617F mutation is most prevalent mutation in the classic BCR-ABL1-negative MPN (95% in PV, 55% in ET, and 65% in PMF), less frequent in unclassified MPNs (20%), CMML (8%) and rare in MDS and AML [51][52][53]. Although cases of CNL have been found occasionally to carry the JAK2V617F mutation, similarly to cytogenetic aberrations, this is a broadly specific finding for myeloid neoplasia and the primary value to date has been to corroborate clonality.…”