The Jak2V617F mutation, PRV-1 overexpression, and EEC formation define a similar cohort of MPD patients

Abstract

Recently, a Jak2V617F mutation has been described in the vast majority of patients with polycythemia vera (PV) as well as in subsets of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The question arises whether this mutation is observed in those patients with ET and IMF who have also displayed previously described molecular markers, notably the ability to form endogenous erythroid colonies (EECs), overexpression of polycythemia rubra vera 1 (PRV-1), and decreased c-Mpl expression. We therefore analyzed the Janus kinase 2 (Jak2) DNA sequence, EEC growth, PRV-1 expression, and c-Mpl (myeloproliferative) levels in a cohort of 78 myeloproliferative disorder (MPD) patients (42 ET, 22 PV, and 14 IMF). Presence of the Jak2V617F mutation was very highly correlated with PRV-1 overexpression and the ability to form EECs in all 3 subtypes of MPDs (P < .001 IntroductionIn 1951, Dameshek 1 coined the term myeloproliferative disorders (MPDs) for a group of 4 clinically related diseases. At the time, this included polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Today, CML is regarded as a separate entity, defined by the t(9;22)(q34;q11) translocation, the "Philadelphia (Ph Ϫ ) chromosome," which results in production of the breakpoint cluster region/Abelson (Bcr/Abl) fusion protein and is not found in the remaining 3 MPD subtypes. 2,3 Several aberrations have been described in patients with PV, ET, and IMF, but none appeared causally linked to the molecular pathogenesis. 4-7 However, 2 alterations, the growth of endogenous erythroid colonies (EECs) and overexpression of the polycythemia rubra vera 1 (PRV-1) mRNA, are highly correlated in individual patients with all 3 subtypes of MPD. 8,9 Therefore, we have proposed that EEC-positive, PRV-1-overexpressing MPD patients constitute a distinct molecular category. 10 In our model, EEC/PRV-1-positive ET and IMF patients are molecularly and clinically more similar to PV patients than to other patients who carry the same clinically defined diagnosis. [9][10][11] The recent description of a point mutation in the Janus kinase 2 (Jak2; Jak2V617F) in the majority of patients with PV as well as subgroups of patients with ET and IMF 12-14 allows us to correlate the presence of this mutation with the occurrence of other markers in individual patients. This analysis can refute or prove the hypothesis that EEC/PRV-1-positive MPD patients share a common molecular determinant of disease etiology. Study design PatientsPeripheral blood samples were obtained from 42 patients with essential thrombocythemia (ET), 22 patients with polycythemia vera (PV), and 14 patients with idiopathic myelofibrosis (IMF). The diagnosis of ET, PV, and IMF were made according to the World Health Organization (WHO) criteria. 15 Venous blood was anticoagulated with EDTA (ethylenediaminetetraacetic acid) or heparin and shipped by courier to the central laboratory without cooling. Maximum time interval between...

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…Altogether persuasive evidence has been produced that even in prodromal stage PV histopathology plays a prominent role for establishing the diagnosis [58] in combination with JAK2V617F and related mutation studies [3,8,10,17,69,70,77,78], the determination of the Epo level [64,[79][80][81] and/or the laboratory intensive as well as timeconsuming cell culture studies [82,83] that are neither absolutely specific for PV [84][85][86] nor standardized for clinical use [87]. All patients developed overt polycythemic PV about 6 months to 2 years later, at the beginning 35 patients may be clinically mimic ET when applying the PVSG criteria [5,7,21].…”

A quantitative assay for JAK2V617F mutation in myeloproliferative disorders by ARMS-PCR and capillary electrophoresis

“…The reported frequency of JAK2 V617F mutation is around 80% (range, 65-100%) in PV, 40% (range, 23-57%) in ET and 55% (range, 35-95%) in IM patients. [5][6][7][8][10][11][12][13][14][15] JAK2 V617F mutation is found in either the heterozygote or the homozygote status, the latter arising from mitotic recombination; [5][6][7][8] there are significant differences in the incidence of homozygosity, which involves about 30% of patients in PV and IM and less than 4% in ET.…”

“…The reported frequency of JAK2 V617F mutation is around 80% (range, 65-100%) in PV, 40% (range, 23-57%) in ET and 55% (range, 35-95%) in IM patients. [5][6][7][8][10][11][12][13][14][15] JAK2 V617F mutation is found in either the heterozygote or the homozygote status, the latter arising from mitotic recombination; [5][6][7][8] there are significant differences in the incidence of homozygosity, which involves about 30% of patients in PV and IM and less than 4% in ET.Whether the presence of the mutation itself can help in identifying biologically and/or clinically distinct subgroups of patients is largely unsettled. 16 In fact, in some of the series published until now, the presence of the mutation has been associated with longer disease duration, propensity to myelofibrosis development (in PV or ET patients) or to leukemia transformation, higher risk of thrombotic complications, advanced age or greater requirement for therapy, whereas others have reported the opposite or no correlation at all; 5,7,8,14,15,17 also, a poorer overall survival has been reported in JAK2 V617F IM patients.…”

Transformed essential thrombocytosis with a JAK2 V617F mutation relapsing as JAK2 mutation-negative leukaemia after allogeneic stem cell transplantation

“…1 The mutation is present in erythroblasts, granulocytes, platelets and multipotent haematopoietic progenitors. 2 The JAK2 mutation has a potential role for the monitoring of residual disease after haematopoietic stem cell transplantation (HSCT) for MPD.…”