Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm essentially characterized by excessive production of platelets. Molecular pathogenesis of ET is linked in approximately half of the patients to intracellular cytokine signaling dysregulation as a result of thrombopoietin receptor or Janus kinase 2 (JAK2) mutations. However, genetic defects underlying cytokine transcription have not been associated with ET. Using molecular cytogenetics and whole-genome array analyses, we uncovered a submicroscopic deletion at 20q13.2 in a JAK2V617F-positive ET patient with an acquired complex chromosome translocation. The deletion encompassed the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene that encodes a transcription factor involved in the regulation of hematopoietic cytokines. RNA interference-mediated suppression of NFATC2 mRNA or pharmacological inhibition of NFATC2 protein with 11R-VIVIT in cultured JAK2V617F-positive SET-2 megakaryocytes increased colony stimulating factor 2 (granulocyte-macrophage) (CSF2) mRNA and promoted cell proliferation. Moreover, impairment of NFATC2-calcineurin interaction with 11R-VIVIT further reduced the transcription of the NFATC2 gene. Antibody-mediated neutralization of CSF2 cytokine in inhibitor-treated cells prevented 11R-VIVIT-induced cell proliferation, indicating that impairment of NFATC2-calcineurin interaction promotes megakaryocyte proliferation through up-regulation of CSF2 transcription. Our results suggest a model in which haplo-insufficiency of NFATC2 cooperates with activation of the JAK-STAT signaling pathway in the pathogenesis of JAK2V617F-positive ET with del(20q). These results further indicate that pathogenesis of ET may be linked to genetic defects of other transcription factor genes involved in the regulation of cytokine expression.

[Recommendations for diagnosis, treatment and monitoring of chronic myeloid leukemia]. / Recomendações para o diagnóstico, tratamento e monitorização da leucemia mielóide crónica.

Chronic Myeloid Leukemia (CML) is a clonal stem cell disease characterized by the expression of the fusion protein bcr-abl1, which has deregulated tirosine-kinase activity. Tyrosine kinase inhibitors (TKIs), and in particular imatinib, introduced fundamental changes in the treatment of CML, becoming, in most cases, the first-line treatment of choice in the chronic phase of this disease. Compared to other available therapies imatinib results in a marked increase in overall survival, tolerability and quality of life. The introduction of second generation TKI, with increased potency against bcr-abl1, expanded the number of therapeutic options for this disease and offers an alternative for patients resistant or intolerant to imatinib or who have progressed to the accelerated phase under this therapy. In order to achieve optimal outcomes, TKI therapy must be managed rigorously, requiring a careful monitoring of treatment response in pre-established time periods, thus permitting disease evaluation and safe decision of the most adequate option. Despite the definition of the criteria for imatinib treatment response, the therapeutic strategies to adopt according to the responses obtained are less clear. The objective of this paper is to review the criteria for CML diagnosis, treatment and monitoring, with recommendations as to the most adequate therapeutic choice according to the response to TKI therapy. The paper also focuses the current lines of investigation and debate areas that in the short term can significantly change the therapeutic scenario in this disease. These recommendations, supported by published scientific evidence and by the clinical practice of the expert panel involved in their elaboration, may constitute an important instrument for a better understanding and standardisation of the treatment and monitoring of CML in Portugal.

[Thrombasthenia of Glanzmann. Vaginal hysterectomy treated with recombinant factor VIIa]. / Trombastenia de Glanzmann. Histerectomia vaginal de urgência tratada com factor VIIa recombinante.

In the present article, regarding a clinical case of Thrombasthenia of Glanzmann with severe anaemia by menometrorrhagia, the authors propose the vaginal hysterectomy and the administration of the recombinant factor VIIa on the immediate pre and postoperative as effective therapeutical alternatives.