Analysis of aberrant signal tansduction in hematological malignancy and development of treatment methods.

本研究的目的是探索新的靶分子，开发对血液系统恶性肿瘤特异有效的信号抑制剂。今年，我们重点研究了JAK 2和JAK 3的突变。7例MPD转化的急性白血病患者中有7例存在JAK 2 V617 F突变。在这些患者中未发现p53、N-RAS和FLT 3突变，但发现了额外的染色体重排，表明JAK 2突变的染色体异常与转化相关。在2例AML（M7）患者中，在假激酶和受体结合结构域位置发现JAK 3突变。因此，在白血病中显性突变的JAK 2和JAK 3是新的靶分子。在FLT 3信号传导中，STAT 5以依赖于突变的方式磷酸化。我们研究了为什么STAT 5在突变型FLT 3信号转导中特异性磷酸化。突变体FLT 3募集Src家族激酶林恩，其在体内和体外磷酸化STAT 5。STAT 5磷酸化水平与FLT 3激酶抑制剂的活性相关。这些数据表明，磷酸化STAT 5是FLT 3靶向治疗中的新的替代标志物。

In this study, we aimed to explore new target molecules and develop signal inhibitors which are specifically effective to hematological malignancies. This year we searched mutation focusing on JAK2 and JAK3. JAK2 V617F mutation was found in 7 of 7 acute leukemia patients who were transformed from MPD. Neither p53, N-RAS and FLT3 mutations were identified in these patients but additional chromosomal rearrangements were found, suggesting addition of chromosomal abnormalities to the JAK2 mutation were associated with the transformation. JAK3 mutations were found in 2 of AML (M7) patients at the position of pseudokinase and receptor binding domains. Accordingly JAK2 and JAK3 which are dominantly mutated in leukemia are new target molecules. In FLT3-signaling, STAT5 is phosphorylated in a mutant-dependent manner. We investigated why STAT5 is specifically phosphorylated in mutant FLT3 signaling. Mutant FLT3 recruited a Src-family kinase Lyn which phosphorylated STAT5 in vivo and in vitro. The level of STAT5 phosphorylation was correlated with the activity of FLT3 kinase-inhibitors. These data suggest that phosphor-STAT5 is a new surrogate marker in FLT3-targeted therapy.