Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Argentina.
Instituto de Investigaciones Hematológicas (IIHEMA), Academia Nacional de Medicina, Buenos Aires, Argentina.
Blood Cells Mol Dis. 2014 Feb-Mar;52(2-3):121-5. doi: 10.1016/j.bcmd.2013.09.002. Epub 2013 Oct 3.
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.
酪氨酸激酶抑制剂（TKIs），如伊马替尼、尼罗替尼和达沙替尼，是目前治疗慢性髓性白血病（CML）的方法。BCR-ABL1 点突变是治疗耐药的主要原因；然而，其他机制也可能参与 TKI 治疗失败。LYN 是一种 src 激酶蛋白，通过 BCR-ABL1 独立的机制调节肿瘤细胞的存活和反应性。PTEN 肿瘤抑制基因在 CML 干细胞中被 BCR-ABL1 下调，其缺失与疾病加速有关。在这项研究中，我们评估了 40 名健康供体（HD）和 139 名 CML 患者中 LYN、PTEN 的表达以及两者比值；其中 88 名患者处于疾病的不同阶段且对 TKI 耐药，51 名患者处于慢性期且被分类为 TKI 的最佳反应者（OR）[40 名接受伊马替尼或尼罗替尼治疗（OR-IN），11 名接受达沙替尼治疗（OR-D）]。当我们分析 LYN 基因表达值时，仅在疾病的晚期观察到增加，然而，当我们分析 LYN 和 PTEN 基因之间的比值时，接受伊马替尼或尼罗替尼治疗的慢性期耐药患者（CP-IN）也显示出显著增加。接受 src 激酶抑制剂达沙替尼治疗的耐药患者表现出与观察到的 HD 相似的比值。此外，在未突变的耐药患者中，LYN/PTEN 比值和 LYN 表达与非 src 激酶抑制剂治疗的 BCR-ABL1 转录水平呈直接显著相关性。我们能够在 CP-IN 中确定 8/35（23%）的病例和在加速期和 blast 期（AP/BC-IN）中确定 4/12（33%）的病例中，耐药可能与 LYN/PTEN 比值的增加有关。我们的数据表明，在接受伊马替尼或尼罗替尼治疗的未突变 CML 患者中，LYN/PTEN 表达比值可能是疾病进展的敏感监测指标。该比值可以检测到与 LYN 表达改变相关的耐药情况，表明改用 src 激酶抑制剂治疗将最适合克服耐药性。
