Consistent up-regulation of Stat3 Independently of Jak2 mutations in a new murine model of essential thrombocythemia

Senyuk, Vitalyi, Rinaldi, Ciro Roberto, Li, Donglan , Cattaneo, Francesca, Stojanovic, Aleksandra, Pane, Fabrizio, Du, Xiaoping, Mahmud, Nadim, Dickstein, Jerome and Nucifora, Giuseppina (2009) Consistent up-regulation of Stat3 Independently of Jak2 mutations in a new murine model of essential thrombocythemia. Cancer research, 69 (1). pp. 262-271. ISSN 0008-5472

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19118011 - Abstract

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Janus-activated kinase 2 (JAK2) mutations are common in myeloproliferative disorders; however, although they are detected in virtually all polycythemia vera patients, they are found in approximately 50% of essential thrombocythemia (ET) patients, suggesting that converging pathways/abnormalities underlie the onset of ET. Recently, the chromosomal translocation 3;21, leading to the fusion gene AML1/MDS1/EVI1 (AME), was observed in an ET patient. After we forced the expression of AME in the bone marrow (BM) of C57BL/6J mice, all the reconstituted mice died of a disease with symptoms similar to ET with a latency of 8 to 16 months. Peripheral blood smears consistently showed an elevated number of dysplastic platelets with anisocytosis, degranulation, and giant size. Although the AME-positive mice did not harbor Jak2 mutations, the BM of most of them had significantly higher levels of activated Stat3 than the controls. With combined biochemical and biological assays we found that AME binds to the Stat3 promoter leading to its up-regulation. Signal transducers and activators of transcription 3 (STAT3) analysis of a small group of ET patients shows that in about half of the patients, there is STAT3 hyperactivation independently of JAK2 mutations, suggesting that the hyperactivation of STAT3 by JAK2 mutations or promoter activation may be a critical step in development of ET.

Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > School of Life Sciences
ID Code:12418
Deposited On:24 Oct 2013 15:56

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