Damdinsuren Anar, Matsushita Hiromichi, Ito Masatoshi, Tanaka Masayuki, Jin Guilan, Tsukamoto Hideo, Asai Satomi, Ando Kiyoshi, Miyachi Hayato
Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Leuk Res. 2015 Dec;39(12):1405-13. doi: 10.1016/j.leukres.2015.09.009. Epub 2015 Sep 10.
Internal tandem duplication (ITD) mutations of the FLT3 gene (FLT3-ITD) are well known to correlate with a poor prognosis in acute myeloid leukemia (AML). We previously reported that FLT3-ITD confers resistance to cytosine arabinoside (Ara-C), a key cytotoxic agent in AML treatments. In order to elucidate the detailed molecular mechanisms underlying the Ara-C resistance induced by FLT3-ITD, we performed a microarray gene expression analysis of the human leukemic cell line K562 transduced with FLT3-ITD (K562/FLT3-ITD) and identified RUNX3 as a downstream target of FLT3-ITD. The transcriptional induction of the RUNX3 expression by FLT3-ITD was noted on a Luciferase assay. The knockdown of the RUNX3 expression in the K562/FLT3-ITD cells increased the sensitivity to Ara-C, and the exogenous expression of RUNX3 per se resulted in the enhancement of Ara-C resistance in the K562 cells. A relationship between the FLT3-ITD-induced RUNX3 expression and Ara-C resistance was also observed in AML cells with an endogenous FLT3-ITD expression. Collectively, these findings demonstrate that RUNX3 is a prerequisite for Ara-C resistance via FLT3-ITD signaling.
FLT3基因的内部串联重复（ITD）突变（FLT3-ITD）与急性髓系白血病（AML）的不良预后密切相关，这是众所周知的。我们之前报道过，FLT3-ITD赋予了对阿糖胞苷（Ara-C）的抗性，阿糖胞苷是AML治疗中的一种关键细胞毒性药物。为了阐明FLT3-ITD诱导的Ara-C抗性背后的详细分子机制，我们对转导了FLT3-ITD的人白血病细胞系K562（K562/FLT3-ITD）进行了微阵列基因表达分析，并确定RUNX3是FLT3-ITD的下游靶点。在荧光素酶测定中发现了FLT3-ITD对RUNX3表达的转录诱导作用。K562/FLT3-ITD细胞中RUNX3表达的敲低增加了对Ara-C的敏感性，而RUNX3本身的外源表达导致K562细胞中Ara-C抗性增强。在具有内源性FLT3-ITD表达的AML细胞中也观察到了FLT3-ITD诱导的RUNX3表达与Ara-C抗性之间的关系。总的来说，这些发现表明RUNX3是通过FLT3-ITD信号传导产生Ara-C抗性的先决条件。
