Crosstalk of FLT3 and integrin signal transduction pathway in acute myeloid leukemia

我们利用32D细胞、MOLM-13细胞、NAMO-2细胞研究了具有结构活性的Flt3对整合素活化的影响。1)Flt3的结构激活诱导白血病细胞系与细胞外基质如纤维连接蛋白的黏附。2)我们的团队建立了具有Flt3/ITD突变的人白血病细胞系NAMO-2，它只能在小鼠骨髓基质细胞系上维持(Abe A et al，Int J hematol 2006)。在NAMO-2细胞上加入Flt3抑制剂可诱导细胞脱离HESS-5.3)本课题组建立了用α-1-Fc嵌合体蛋白激活β-1整合素的方法。表达Flt3/ITD的32D细胞与Flt3抑制剂灭活的α4β1整合素共同孵育。在具有Flt3/ITD突变的MOLm-13中也观察到了同样的结果。在32D-Flt3/ITD细胞中加入Flt3配体可诱导α4β1整合素的激活。4)αvβ3整合素的激活是由PI3K介导的，随后整合素与细胞外基质蛋白的结合增加。新的整合素与细胞外基质蛋白结合可诱导JNK/SAPK的激活。这些观察证实了整合素和其他激酶信号转导通路之间的串扰。

We have investigated the effects of constitutive active FLT3 on activation of integrin by using 32D cells, MOLM-13, NAMO-2 cells.1) Constitutive activation of FLT3 induced the adhesion of leukemia cell lines on extracellular matrix such as fibronectin.2) Our group established the human leukemia cell line NAMO-2 that has FLT3/ITD mutation and can be maintained only on the mouse bone marrow stromal cell line (Abe A et al, Int J Hematol 2006). Addition of FLT3 inhibitor onto NAMO-2 induced the detachment of cell line from the HESS-5.3) Our group established the α4β1 integrin activation assay by VCAM-1-Fc chimera protein. Incubation of 32D cells expressing FLT3/ITD with FLT3 inhibitor inactivated α4β1 integrin. Same results were observed in MOLM-13, which has FLT3/ITD mutation. Addition of FLT3 ligand to 32D-FLT3/ITD cells induced the activation of α4β1 integrin.4) αvβ3 integrin activation is mediated by PI3K and is followed by increase in integrin binding to extracellular matrix proteins. The new integrin binding to extracellular matrix protein induce the activation of JNK/SAPK. These observations demonstrated the cross talk of integrin and other kinases signal transduction pathways.