Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation

Gangat, Naseema; Strand, Jacob J.; Li, Chin Yang; Wu, Wenting; Pardanani, Animesh; Tefferi, Ayalew

doi:10.1111/j.1365-2141.2007.06674.x

Cited by 134 publications

(123 citation statements)

References 32 publications

(42 reference statements)

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“…[69][70][71][72] By contrast, a leukemogenic potential of hydroxyurea (HU) has not been shown in clinical trials, although there is evidence showing that the sequential use of HU and other cytoreductive drugs (alkylating agents, radioactive phosphorus) increases the risk of AL/MDS. [72][73][74][75] In addition, several retrospective studies did not find an increased risk of AL in PV and ET treated with HU alone, [76][77][78] and similar conclusions were drawn from a recent meta-analysis of HU therapy in sickle cell anemia. 79 Still, very long-term results of prospective studies in HU-treated MPN patients with more than 10 years of follow-up showed a cumulative incidence of AL/MDS of more than 10% beyond 12 years of follow-up, suggesting that the risk of leukemic evolution could be higher than reported earlier in studies with shorter follow-up.…”

Section: Ifn-a and Leukemic Evolutionsupporting

confidence: 51%

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

2008

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Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-a2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-a in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-a induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-a the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-a on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-a in JAK2-mutated MPN.

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Section: Ifn-a and Leukemic Evolutionsupporting

confidence: 51%

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

2008

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“…It is not clear whether leukocytosis, which is seen in certain MPN patients and which appears to be associated with certain complications or evolution toward leukemia, 102 may be due to the pathologic activation of G-CSFR by JAK2 V617F. Granulocytes from patients with MPNs presented altered gene expression promoted by JAK2 V617F expression and confirmed a recapitulation of cytokine receptor signaling, resembling profiles of granulocytes activated by G-CSF.…”

Section: Spotlightmentioning

confidence: 95%

“…It can be noted that for this receptor, a very delicate balance has been identified between the activation of STAT3, required for differentiation and inducing a stop in cell growth (necessary for differentiation), and STAT5, which promotes proliferation. 102 Binding of SOCS3 through its SH2 domain to a phosphorylated tyrosine residue in the receptor's cytosolic end specifically downregulates STAT5 signaling. Deletion of the cytosolic region, which contains the binding site for SOCS3, leads to enhanced STAT5-to-STAT3 signaling ratio, 102 and this is associated with evolution toward acute myeloid leukemia of patients with severe congenital neutropenia.…”

Section: Spotlightmentioning

confidence: 99%

“…102 Binding of SOCS3 through its SH2 domain to a phosphorylated tyrosine residue in the receptor's cytosolic end specifically downregulates STAT5 signaling. Deletion of the cytosolic region, which contains the binding site for SOCS3, leads to enhanced STAT5-to-STAT3 signaling ratio, 102 and this is associated with evolution toward acute myeloid leukemia of patients with severe congenital neutropenia.…”

Section: Spotlightmentioning

confidence: 99%

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Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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“…Post-polycythemia vera myelofibrosis (post-PV MF) is a long term clinical outcome in around 10 % of patients with polycythemia vera (PV) [1,2]. No clear risk factors have been identified for such a transformation.…”

Section: Introductionmentioning

confidence: 99%

A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis

Değertekin

Akyürek

Yağcı

2012

Indian J Hematol Blood Transfus

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Polycythemia vera is a clonal proliferative disorder of the bone marrow that could possibly evolve into myelofibrosis in its natural course. Progression to myelofibrosis is usually a late stage complication and presents clinically with refractory cytopenias and extramedullary hematopoiesis (EMH). EMH can occur in any tissue during the course of post-polycythemic myelofibrosis. However, skin and cardiac involvements seems to be very rare. We present a 56-year-old woman with post-polycythemic myelofibrosis refractory to treatment, developing EMH after splenectomy in various organs, exceptionally the skin and the heart. Along with the case, the clinical presentations, treatment options, prognostic significance of EMH and the role of cytogenetics is discussed in the light of the literature.

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Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation

Abstract: highlighted the prognostic relevance of leucocytosis on various aspects of the disease in PV.

Cited by 134 publications

References 32 publications

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

Aberrant signal transduction pathways in myeloproliferative neoplasms

A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis

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