Expression of LYN and PTEN genes in chronic myeloid leukemia and their importance in therapeutic strategy
Expression of LYN and PTEN genes in chronic myeloid leukemia and their importance in therapeutic strategy
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DOI：
10.1016/j.bcmd.2013.09.002
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发表时间：
2014-02-01
影响因子：
2.3
通讯作者：
Larripa, Irene
中科院分区：
文献类型：
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作者：
Ferri, Cristian;Bianchini, Michele;Larripa, Irene
酪氨酸激酶抑制剂(TKIs)，伊马替尼、尼洛替尼和达沙替尼，是目前治疗慢性粒细胞白血病(CML)的主要药物。Bcr-abl1点突变是耐药的主要原因；然而，其他机制可能与TKI治疗失败有关。Lyn是一种src蛋白，通过bcr-abl1非依赖机制调节肿瘤细胞的存活和反应。慢性粒细胞白血病干细胞中抑癌基因PTEN受bcr-abl1基因下调，其缺失与疾病进展有关。在这项研究中，我们检测了40例健康献血者(HD)和139例CML患者中Lyn和PTEN的表达及其两者的比例，其中88例在疾病的不同阶段对TKI耐药，51例在慢性期被归类为对TKI的最佳应答者(OR)[40例接受伊马替尼或尼洛替尼(OR-IN)治疗，11例接受达沙替尼(OR-D)治疗]。当我们分析Lyn基因的表达值时，只有在疾病的晚期才观察到Lyn基因的增加，然而，当我们分析Lyn和PTEN基因的比率时，伊马替尼或尼洛替尼治疗的慢性期耐药组(CP-IN)也显示出显著的增加。接受src激酶抑制剂达沙替尼治疗的耐药患者的比例与观察到的HD患者相似。此外，在接受非src激酶抑制剂治疗的未突变耐药患者中，Lyn/PTEN比率和Lyn表达与bcr-abl1转录本水平直接相关。我们能够识别出8/35(23%)的CP-IN和4/12(33%)的加速期和急变期(AP/BC-IN)病例，在这些病例中，耐药可能与Lyn/PTEN比率的增加有关。我们的数据表明，Lyn/PTEN的表达比率可能是对接受伊马替尼或尼洛替尼治疗的未突变CML患者疾病进展的敏感监测。这一比率可以检测到耐药性与Lyn表达变化有关的病例，这表明改用src激酶抑制剂治疗最适合克服耐药性。(C)2013 Elsevier Inc.保留所有权利。
Tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, are the current treatment of chronic myeloid leukemia (CML). BCR-ABL1 point mutations are the principal cause of resistance to treatment; however other mechanisms could be involved in failure to TKI therapy. LYN is a src kinase protein that regulates survival and responsiveness of tumor cells by a BCR-ABL1 independent mechanism. PTEN tumor suppressor gene is downregulated by BCR-ABL1 in CML stem cells and its deletion is associated with acceleration of disease. In this study we evaluated the expression of LYN, PTEN and the ratio of both genes in 40 healthy donors (HD) and in 139 CML patients; 88 of them resistant to TKI in different phases of disease and 51 in chronic phase classified as optimal responders (OR) to TKI [40 treated with imatinib or nilotinib (OR-IN) and 11 treated with dasatinib (OR-D) therapy]. When we analyzed the gene expression values of LYN, an increase was observed only in advanced stages of the disease, however, when we analyzed the ratio between LYN and PTEN genes, the group of resistant patients in chronic phase in imatinib or nilotinib treatment (CP-IN) also showed a significant increase. Resistant patients treated with dasatinib, a src kinase inhibitor, presented a similar ratio to the observed in HD. In addition, the LYN/PTEN ratio and the LYN expression showed a direct significant correlation with BCR-ABL1 transcript levels in unmutated resistant patients treated with non-src kinase inhibitors. We were able to identify 8/35 (23%) of cases in CP-IN and 4/12(33%) in accelerated phase and blast phase (AP/BC-IN), in which resistance could be associated with an increase in the ratio of the LYN/PTEN. Our data suggest that the LYN/PTEN expression ratio may be a sensitive monitor of disease progression in unmutated CML patients under imatinib or nilotinib treatment. This ratio could detect cases when resistance is related to altered LYN expression, suggesting that the treatment change to a src kinase inhibitor would be most suitable to overcome resistance. (C) 2013 Elsevier Inc. All rights reserved.