The recent discovery of a recurrent activating Janus tyrosine kinase (JAK2) mutation (JAK2VG17F) in all 3 classic MPDs offers another opportunity for refining current diagnoses and disease classifications.
We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.
In the past 3 months, 7 different studies have Independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abi-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome.
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).
The current observation strengthens the specific association between JAK2V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.
Although the V617FJAK2 mutation has been described by several groups to be associated with classical myeloproliferative disorders (MPD), this same mutation has been detected with a low incidence in atypical MPD, such as CNL.
However, it is very clear that some patients with classical PV lack the JAK2 V617F mutation, while some patients with other chronic myeloproliferative disorders such as idiopathic myelofibrosis (IMF) and essential thrombocytosis (ET) also express the JAK2V617F mutation.
We conclude that multiple molecular abnormalities are involved in the pathogenesis of the MPDs and that aberrant Mpl expression may be a common denominator of aberrant signaling in both the JAK2V617F-positive and JAK2V617F-negative MPDs.
Transcription factor Fli-1 expression by bone marrow cells in chronic myeloproliferative disorders is independent of an underlying JAK2 (V617F) mutation.
Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response.
Among these 22 families, the absence of the JAK2 mutation both in purified T and B cells in 13 unrelated patients and the observation of variable ratios of the JAK2 mutant allele in patient leucocytes indicated that the Val617PheJAK2 mutation was acquired in familial MPDs.
This indicates that JAK2 V617-positive ET patients, diagnosed according to the PVSG criteria, represent a "forme fruste of PV" consistent with early PV mimicking ET (JAK2V617F trilinear MPD).
Substitution of a valine for a phenylalanine destabilizes the JH2 domain of JAK2 causes loss of the auto-inhibitory activity of this domain and explains some of the biological phenomena observed in patients with myeloproliferative disorders (MPD).
A point mutation in the Janus tyrosine kinase 2 (JAK2) gene has been described in patients with chronic myeloproliferative disorders (MPD), but the clinical significance of JAK2(V617F), which may be harbored in either the heterozygote or homozyote status, is still largely undefined.
The current findings indicated that the JAK2 (V617F) mutation represents an acquired somatic mutation in patients with familial chronic myeloproliferative disorders and probably occurs as a secondary genetic event in the background of preexisting clonal hematopoiesis.
We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis.
However, until the recent description of the constitutively activating V617F point mutation of the Janus 2 tyrosine kinase (JAK2)--a high-frequency molecular marker that is extremely specific for clonal chronic myeloproliferative disorders--distinction of PV from secondary erythrocytosis or other conditions has often been difficult.