FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression
FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression
复制标题
DOI：
10.1016/j.bbrc.2009.10.094
复制
发表时间：
2009-12-18
影响因子：
3.1
通讯作者：
Miyachi, Hayato
中科院分区：
文献类型：
--
作者：
Jin, Guilan;Matsushita, Hiromichi;Miyachi, Hayato
FMS相关酪氨酸激酶3-内部串联重复(Flt3-ITD)与标准联合化疗的急性髓系白血病(AML)的难治性密切相关。为了明确Flt3-ITD在急性髓系白血病细胞耐药中的作用，分别建立了表达Flt3-ITD的小鼠和人髓系细胞系HF6/Flt3-ITD和K562/Flt3-ITD细胞。这两种细胞株都对急性髓细胞白血病的必需剂--嘧啶类似物阿糖胞苷(Ara-C)产生特异性耐药，同时平衡核苷转运体1(ENT1)的表达下调，而平衡核苷转运体1是负责细胞摄取阿糖胞苷的转运体。在K562/Flt3-ITD细胞中，ENT1启动子活性和细胞对Ara-C的摄取均降低，并被Flt3抑制剂PKC412所恢复。此外，缺氧诱导因子Iα亚单位(HIF1a)转录产物在K562/Flt3-ITD细胞中的表达上调，HIF-1α的诱导降低了K562细胞中ENT1基因的启动子活性。综上所述，这些发现表明，Flt3-ITD通过抑制ENT1的表达而特异性地诱导白血病细胞中的Ara-C耐药，可能是通过上调HIF-1α，同时也部分解释了由于对包括Ara-C在内的标准化疗方案的耐药，患有Flt3-ITD的AML预后不良的部分原因。(C)2009 Elsevier Inc.保留所有权利。
Fms-related tyrosine kinase 3-internal tandem duplications (FLT3-ITD) are strongly associated with the refractory nature of acute myeloid leukemia (AML) by the standard combined chemotherapy. FLT3-ITD-expressing murine and human myeloid cell lines, HF6/FLT3-ITD and K562/FLT3-ITD cells, respectively, were developed in order to clarify whether FLT3-ITD is involved in the resistance to cytotoxic agents in AML. Both of these cell lines were specifically resistant to the pyrimidine analogue cytosine arabinoside (ara-C), an essential agent for AML, accompanied by the downregulation of equilibrative nucleoside transporter 1 (ENT1), a transporter responsible for the cellular uptake of ara-C. The ENT1 promoter activity and the cellular uptake of ara-C were reduced in K562/FLT3-ITD cells, and rescued by pretreating the cells with PKC412, a FLT3 inhibitor. In addition, the expression of hypoxia inducible factor I alpha subunit (HIF1A) transcripts was upregulated in K562/FLT3-ITD cells, and the induction of HIF-1 alpha reduced the promoter activity of ENT1 gene in K562 cells. Taken together, these findings Suggest that FLT3-ITD specifically induces ara-C resistance in leukemic cells by the repression of ENT1 expression, possibly through the upregulation of HIF-1 alpha, while also partially accounting for the poor prognosis of AML with FLT3-ITD due to resistance to the standard chemotherapy protocols which include ara-C. (C) 2009 Elsevier Inc. All rights reserved.