A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide
A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide
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DOI：
10.1073/pnas.0811267106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
List, Alan
中科院分区：
文献类型：
--
作者：
Wei, Sheng;Chen, Xianghong;List, Alan
来那度胺是第一个批准用于治疗骨髓增生异常综合征（MDS）的核型选择性治疗药物，因为染色体5 q缺失[del（5 q）]患者的红细胞和细胞遗传学应答率较高。尽管在del（5 q）表型的发病机制中涉及RPS 14基因和共同缺失区（CDR）内编码的其他基因的单倍不足，但来那度胺的核型特异性的分子基础仍无法解释。我们的分析集中在CDR内编码的可能的单倍缺陷酶靶点上，这些酶靶点在细胞周期调控中起关键作用。我们发现，双重特异性磷酸酶Cdc 25 C和PP 2Ac α，这是G（2）-M检查点的辅助调节剂，被来那度胺抑制。与具有交替核型的MDS和急性髓性白血病（AML）标本相比，具有del（5 q）的MDS和AML标本的基因表达较低。来那度胺可直接（Cdc 25 C）或间接（PP 2A）抑制磷酸酶活性，并相应保留抑制性磷酸酪氨酸残基。用来那度胺处理del（5 q）AML细胞可诱导G（2）阻滞和凋亡，而对非del（5 q）AML细胞无影响。在U937和原代非del（5 q）MDS细胞中，Cdc 25 C和PP 2Ac α基因表达的小干扰RNA（shRNA）抑制再现了del（5 q）对来那度胺的敏感性，并诱导G（2）阻滞和凋亡。这些数据确定了来那度胺可重复Cdc 25 C和PP 2Ac α磷酸酶的等位基因单倍缺陷在del（5 q）MDS的选择性药物敏感性中的作用。
Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Ac alpha, which are coregulators of the G(2)-M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G(2) arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Ac alpha gene expression recapitulated del( 5q) susceptibility to lenalidomide with induction of G(2) arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Ac alpha phosphatases in the selective drug sensitivity of del(5q) MDS.