| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Research Abstract |
Myeloproliferative neoplasms (MPN), a group of hematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the TEL-Lyn fusion gene in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of TEL-Lyn into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged Lyn kinase in the pathogenesis of MPN with myelofibrosis. In this study, we demonstrated that the direct activation of STAT5 by TEL-Lyn is crucial for the development of MPN. TEL-Lyn was constitutively active as a kinase through autophosphorylation. In TEL-Lyn-expressing cells, STAT5 was activated in a JAK2-independent manner. TEL-Lyn interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, TEL-Lyn did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of TEL-Lyn to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of TEL-Lyn and unveil the Lyn-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukemia.
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