GATA1 Is Overexpressed in Patients with Essential Thrombocythemia and It Is Normalized By Anagrelide Treatment

Lilia Brown, Ciaren Graham, Yvette Martyn, Ciro Rinaldi

Research output: Contribution to journalArticle

Abstract

GATA1 is the founding member of the GATA transcription factor family and is essential for cell maturation and differentiation within the erythroid and megakaryocytic lineages. GATA1 is a pleotropic transcription factor, whose expression is essential in these lineages; its function depends upon its ability to bind to both DNA and protein partners. Disturbance of either of these functions causes severe hematopoietic dysfunction and can result in blood disorders, such as thrombocytopenia, anaemia and even leukaemia. Ectopic expression of GATA1 in the murine myeloid cell line M1 induces c-Mpl appearance and megakaryocyte (MK) differentiation. The same phenomenon has been showed to occur in hematopoietic stem cells; in that forced increased expression of GATA1 blocked self-renewal and induced the exclusive generation of MegE lineages. Several studies, have suggested a connection between GATA1 and myeloproliferative neoplasia (MPN). We previously reported that high GATA1 transcript levels are found in the bone marrow of patients with ET and PV, independent of JAK2V617F or CALR mutation status. However, over expression of GATA1 is not seen in other MPNs.Anagrelide (ANA) has been proven to be an effective drug in reducing platelet count and thrombotic risk in management of ET and PMF patients. However, the mechanism by which this drug induces this effect is still unclear. Recently Erusalimsky and colleges have reported that ANA results in down-modulation of GATA1 and its co-factor FOG1 in MK during in vitro differentiation.In this study, we analysed the expression of GATA1 in peripheral blood (PB) samples from 38 patients with ET and compared the levels of expression before and after treatment with common cytoreductive agents such as hydroxyurea (HU) and ANA.We confirmed the data obtained in BM, with a significant up-regulation of GATA1 in ET compared to controls. When we measured the expression of GATA1 before and during treatment with ANA, there was a significant reduction of the GATA1 expression at 3 and 6 months of therapy, concomitant with a reduction in platelets (PLT) counts. Interestingly, this was not equally observed in patients treated with HU, where despite reduction in PLT counts, the GATA1 levels rose. Furthermore, when we analysed patients on combination treatment ANA + HU, GATA1 expression reduced only when patients were taking ANA. When ANA treatment was stopped and the patient continued only on HU, GATA1 levels rose again. This data suggests a direct effect of ANA on GATA1 expression.Although, no direct correlation between GATA1 expression and CALR mutations was found. However, a significant up regulation of CALR mRNA was observed independently from the CALR mutational status.GATA1 may represent a generic molecular marker in ET and a possible additional diagnostic criteria in thrombocytosis. GATA1 overexpression is independent from JAK2 mutations, and responds specifically to ANA therapy suggesting a role in monitoring therapy response.Disclosures No relevant conflicts of interest to declare.↵* Asterisk with author names denotes non-ASH members.
Original languageEnglish
JournalBlood
Volume124
Issue number21
Publication statusPublished - 06 Dec 2014

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