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

在本研究中，我们旨在探索新的靶点分子，开发对血液系统恶性肿瘤特异性有效的信号抑制剂。今年我们研究了JAK2和JAK3上的突变。在7例由MPD转化而来的急性白血病患者中，有7例发现JAK2 V617F突变。在这些患者中没有发现p53、N-RAS和FLT3突变，但发现了额外的染色体重排，这表明JAK2突变的染色体异常与转化有关。在2例AML （M7）患者中，在假激酶和受体结合域的位置发现JAK3突变。因此，在白血病中显性突变的JAK2和JAK3成为新的靶分子。在flt3信号传导中，STAT5以突变依赖的方式磷酸化。我们研究了为什么STAT5在突变FLT3信号中被特异性磷酸化。突变体FLT3招募了src家族激酶Lyn，该激酶在体内和体外磷酸化STAT5。STAT5磷酸化水平与FLT3激酶抑制剂活性相关。这些数据表明，在flt3靶向治疗中，磷酸化stat5是一个新的替代标记物。

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.