Analysis of the FLT3/FLT3 ligand system in ALL with 11q23 translocations

分析了Flt3配体(FL)诱导的11q23易位ALL细胞周期停滞和对抗白血病药物耐药性产生的机制。在FL存在下培养3天后，11q23易位的KOCL-58细胞被诱导进入GO/GI停滞状态，CDK抑制剂p27表达上调，STATS去磷酸化。在FL诱导的细胞周期停滞中，细胞对柔红霉素(DNR)和阿糖胞苷(AraC)表现出耐药性。与高水平表达膜结合型FL的骨髓基质细胞共培养时，细胞可被诱导进入GO/GI停滞状态，并对柔红霉素和阿糖胞苷表现耐药。在抗FL抗体的存在下，这一作用被部分消除。因此，所有带有11q23易位的细胞在体内被诱导进入耐化疗的静止状态，当它们与产生FL的骨髓基质细胞黏附时，无论是膜结合型还是分泌型。这种Flt3/FL系统可能与11q23易位ALL早期复发的骨髓残留病的形成有关。

Mechanism of the FLT3 ligand (FL) -induced cell cycle arrest and acquisition of resistance against anti-leukemic drugs in ALL with 11q23 translocations was analyzed. Three days after culture in the presence of FL, KOCL-58 cell line with 11q23 translocation was induced into GO/GI arrest with up-regulation of CDK inhibitor p27 and dephosphorylation of STATS. In FL-induced cell cycle arrest, the cell line showed resistance against daunorubicin (DNR) or cytosine arabinosid (AraC). When cocultured with bone marrow stromal cell line expressing membrane-bound form of FL at high levels, the cell line was induced into GO/GI arrest and showed resistance to DNR or AraC. This effect was partially abrogated in the presence of anti-FL antibody. Thus, ALL cells with 11q23 translocations are induced into quiescent state resistant to chemotherapy in vivo when they adhere to bone marrow stromal cells producing FL irrespective of membrane-bound form or secretary form. This FLT3/FL system may be associated with the formation of minimum residual disease in bone marrow resulting in early relapse of ALL with 11q23 translocations.