| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
In pro-B cell acute lymphoblastic leukemia (ALL), expression of the E2A-HLF fusion gene as a result of the t(17;19)(q22;p13) is associated with poor prognosis, hypercalcemia, and hemorrhagic complications. We previously reported that the E2A-HLF fusion protein protects interleukin (IL)-3-dependent lymphoid cells from apoptosis caused by cytokine starvation. Here, we report that annexin II, a surface phospholipid-binding protein and one of the proposed causes of the hemorrhagic c9mplications of acute promyelocytic leukemia (APL), is also implicated in t(17;19)^+ ALL. Annexin II was expressed at high levels in APL cells and in each of four t(17;19)^+ leukemia cell lines, and annexin II expression was I. induced by enforced expression of E2A-HLF in leukemia cells. In IL-3-dependent cells, we found that annexin II expression was regulated by IL-3 mainly by Ras pathways, including Ras/phosphatidylinositol 3-kinase pathways. Moreover, E2A-HLF increased annexin II expression in 11-3-depe ndent cells in the absence of the cytokine. These findings indicate that E2A-HLF induces annexin II by substituting for cytokines that activate downstream pathways of Ras. These findings indicate that annexin II is a downstream target of the E2A-HLF oncoprotein. However, surface expression levels of annexin II among leukemia cells with t(17;19) varied in a manner that suggests that annexin II plays a role in the hypercalcemia or leukemic invasion rather than in the coagulopathy associated with this type of ALL.
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