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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide
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A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide

机译：来那度胺选择性抑制5q MDS缺失中磷酸酶单倍缺乏的关键作用

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摘要

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 PP2Acα, which are coregu-lators 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 karyo-types. 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 PP2Acα 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 PP2Acα phosphatases in the selective drug sensitivity of del(5q) MDS.
机译：来那度胺是第一种被批准用于治疗骨髓增生异常综合症（MDS）的核型选择性治疗药物，这是由于5q染色体缺失[del（5q）]患者的红细胞和细胞遗传学反应率很高。尽管RPS14基因的单倍剂量不足和其他在常见缺失区（CDR）中编码的单核苷酸不足与del（5q）表型的发病机理有关，但来那度胺核型特异性的分子基础仍无法解释。我们将分析的重点放在CDR内编码的可能的单倍酶上，这些酶在细胞周期调控中起关键作用。我们表明，来那度胺可以抑制双重特异性磷酸酶Cdc25C和PP2Acα，它们是G_2-M检查点的核心调控因子。与具有其他核型的人相比，在具有del（5q）的MDS和急性髓细胞性白血病（AML）标本中，基因表达较低。来那度胺可直接（Cdc25C）或间接（PP2A）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（5q）AML细胞可诱导G_2阻滞和凋亡，而对nondel（5q）AML细胞无作用。 Cdc25C和PP2Acα基因表达的小干扰RNA（shRNA）抑制概括了U937和原发性nondel（5q）MDS细胞中del（5q）对来那度胺的敏感性，并诱导了G_2阻滞和凋亡。这些数据建立了来那度胺可抑制的Cdc25C和PP2Acα磷酸酶的等位基因单倍缺失在del（5q）MDS选择性药物敏感性中的作用。

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  • 作者

    Sheng Wei; Xianghong Chen; Kathy Rocha; P. K. Epiing-Burnette; Julie Y. Djeu; Qing Liu; John Byrd; Lubomir Sokol; Nick Lawrence; Roberta Pireddu; Gordon Dewald; Ann Williams; Jaroslaw Maciejewski; Alan List;

  • 作者单位

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Ohio State University, Columbus, OH 43210;

    Ohio State University, Columbus, OH 43210;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

    Mayo Clinic, Rochester, MN55905;

    University of Tampa, Tampa, FL33606;

    Taussig Cancer Center, Cleveland, OH44195;

    Immunology Program and Malignant Hematology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cancer treatment; myelodysplastic syndromes; drug sensitivity Cdc25C; PP2A;

    机译：癌症治疗;骨髓增生异常综合症;药物敏感性Cdc25C;PP2A;

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