1,721,164 research outputs found
Role of thrombopoietin in mast cell differentiation
No full textMast cells are important elements of the body response to
foreign antigens, being those represented either by small molecules (al-
lergic response) or harbored by foreign microorganisms (response to par-
asite infection). These cells derive from hematopoietic stem/progenitor
cells present in the marrow. However, in contrast with most of the other
hematopoietic lineages, mast cells do not differentiate in the marrow
but in highly vascularized extramedullary sites, such as the skin or the
gut. Mast cell differentiation in the marrow is activated as part of the
body response to parasites. We will review here the mast cell differen-
tiation pathway and what is known of its major intrinsic and extrinsic
control mechanisms. It will also be described that thrombopoietin, the
ligand for the Mpl receptor, in addition to its pivotal rule in the control
of thrombocytopoiesis and of hematopoietic stem/progenitor cell prolif-
eration, exerts a regulatory function in mast cell differentiation. Some
of the possible implications of this newly described biological activity of
thrombopoietin will be discussed
The rate of transformation from JAK2-mutated ET to PV is influenced by an accurate WHO-defined clinico-morphological diagnosis
No full textEssential thrombocythemia with high hemoglobin levels according to the revised WHO classification
No full textDiscriminating between essential thrombocythemia and masked polycythemia vera in JAK2 mutated patients
No full textIn patients not meeting the required hematocrit (HCT) or hemoglobin (Hb) thresholds according to BCSH and the WHO diagnostic criteria, the diagnosis of masked polycythemia vera (mPV) has been proposed. A comparison of HCT or Hb values with the expression of JAK2V617F, JAK2 exon 12, and CALR mutations in strictly WHO-defined 257 overt PV and 140 mPV (59 mPV according to BCSH) and 397 patients with essential thrombocythemia (ET) was performed. Hb and HCT thresholds of mPV patients were significantly higher than JAK2V617F ET (P < 0.0001). The best cut-off for Hb to discriminate JAK2-mutated ET from PV was 16.5 g/dL for males and 16.0 g/dL for females. For HCT, this was 49% in males and 48% in females. The proportion of patients correctly classified as ET or PV when regarding Hb or HCT levels was 95% in males and 93% in females and 94% in both males and females, respectively
JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations.
No full textThe discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents
No correlation of intensity of phlebotomy regimen with risk of thrombosis in polycythemia vera: evidence from European Collaboration on Low-Dose Aspirin in Polycythemia Vera and Cytoreductive Therapy in Polycythemia Vera clinical trials
No full text
Overexpression of microRNA-16-2 contributes to the abnormal erythropoiesis in polycythemia vera.
No full textDeregulated expression of microRNAs is associated with neoplasia. Here, we show that mature miR-16 levels are abnormally increased in CD34(+) cells of patients with polycythemia vera as a consequence of preferential expression of miR-16-2 on chromosome 3 rather than of miR-16-1 on chromosome 13. Forced expression of miRNA-16 in normal CD34(+) cells stimulated erythroid cell proliferation and maturation. Conversely, exposure of polycythemia vera CD34(+) cells to small interfering RNA against pre-miR-16-2 reduced erythroid colonies and largely prevented formation of erythropoietin-independent colonies; myeloid progenitors remained unaffected. Experiments with knock down of JAK2 indicated that overexpression of miR-16 was independent of JAK/STAT pathway activation. Mice injected with an miR-16 antagomir showed a blunted erythroid response to exogenous erythropoietin, which indicates a role of miR-16 in normal erythropoiesis. These data suggest that deregulation of miR-16-2 contributes to abnormal expansion of erythroid lineage in polycythemia vera. However, the mechanisms for miR-16-2 overexpression remain to be elucidated, because no genetic abnormalities at the miR-16-2 locus were discovered
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