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

在这项研究中，我们的目标是探索新的靶分子，并开发对血液系统恶性肿瘤特异有效的信号抑制药。今年，我们搜索了JAK2和JAK3上的突变。7例MPD转化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突变之外的染色体异常与转化有关。在2例急性髓系白血病(M7)患者中，在假性激酶和受体结合区位置发现JAK3突变。因此，在白血病中主要突变的JAK2和JAK3成为新的靶向分子。在Flt3信号转导中，STAT5以突变依赖的方式被磷酸化。我们研究了为什么STAT5在突变的Flt3信号中被特异性磷酸化。突变的Flt3在体内和体外招募了一个使STAT5磷酸化的Src家族的蛋白Lyn。STAT5的磷酸化水平与Flt3激酶抑制物的活性相关。这些数据表明，在Flt3靶向治疗中，p-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.