Fms-like tyrosine kinase 3 ligand stimulation induces MLL-rearranged leukemia cells into quiescence resistant to antileukemic agents
Fms-like tyrosine kinase 3 ligand stimulation induces MLL-rearranged leukemia cells into quiescence resistant to antileukemic agents
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DOI：
10.1158/0008-5472.can-07-0105
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Sugita, Kanji
中科院分区：
文献类型：
--
作者：
Furuichi, Yoshiyuki;Goi, Kumiko;Sugita, Kanji
Fms样酪氨酸激酶3（FLT3）在伴有混合谱系白血病（MLL）基因重排且对化疗耐药的急性淋巴细胞白血病中高表达。我们研究了FLT3配体（FL）对具有不同核型异常的B前体白血病细胞系的生物学效应，发现与其他白血病细胞系相比，9株具有野生型FLT3的MLL重排细胞系中，有9株的增殖受到FL以剂量依赖的方式显著抑制。这种抑制是由于诱导了G0 - G1期阻滞。在FL刺激后，阻滞的白血病细胞中显示出p27因蛋白降解受抑制而显著上调，以及组成性信号转导子和转录激活子5磷酸化被阻断。重要的是，FL处理不仅使细胞系，而且使原发性MLL重排白血病细胞对化疗药物产生耐药。MLL重排的白血病细胞黏附于以膜结合形式表达FL的骨髓基质细胞系时，被诱导进入对化疗药物耐药的静止状态，但在中和性抗FL抗体存在的情况下，其化疗敏感性显著恢复。白血病细胞与高水平表达FL的骨髓基质细胞之间的FL/FLT3相互作用，至少在一定程度上应是导致MLL重排白血病在骨髓中持续存在微小残留病的原因。
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in acute lymphoblastic leukemia with the mixed-lineage leukemia (MLL) gene rearrangement refractory to chemotherapy. We examined the biological effect of FLT3-ligand (FL) on IS Bprecursor leukemic cell lines with variable karyotypic abnormalities, and found that nine of nine MLL-rearranged cell lines with wild-type FLT3, in contrast to other leukemic cell lines, are significantly inhibited in their proliferation in a dose-dependent manner by FL. This inhibition was due to induction of the GO-G, arrest. A marked up-regulation of p27 by suppression of its protein degradation and an abrogation of constitutive signal transducers and activators of transcription 5 phosphorylation were revealed in arrested leukemia cells after FL stimulation. Importantly, FL, treatment rendered not only cell lines but also primary leukemia cells with MLL rearrangement resistant to chemotherapeutic agents. WLLrearranged leukemia cells adhering to the bone marrow stromal cell line, which expresses FL, as the membrane-bound form, were induced to quiescent state resistant to chemotherapeutic agents, but their chemosensitivity was significantly restored in the presence of neutralizing anti-FL, antibody. The FL/FLT3 interaction between leukemia cells and bone marrow stromal cells expressing FL, at high levels should contribute, at least in part, to persistent minimal-residual disease of MLL-rearranged leukemia in bone marrow.