ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells.
ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells.
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DOI：
10.1016/j.stemcr.2018.01.015
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发表时间：
2018-03-13
影响因子：
5.9
通讯作者：
Kurokawa M
中科院分区：
文献类型：
--
作者：
Miyauchi M;Koya J;Arai S;Yamazaki S;Honda A;Kataoka K;Yoshimi A;Taoka K;Kumano K;Kurokawa M
参与耐药和复发的癌症干细胞的性质对临床结果有显著影响。虽然酪氨酸激酶抑制剂（TKI）已显着改善慢性髓性白血病（CML）患者的生存率，但由于TKI耐药CML干细胞，TKI尚未完全治愈CML。此外，在TKI缓解最佳的CML患者中，无法预测TKI停药后的复发。在我们的研究中，从CML诱导的多能干细胞衍生的CML干细胞模型鉴定了ADAM 8作为TKI抗性CML细胞的抗原。抑制ADAM 8的表达或金属蛋白酶活性恢复了原代样本中的TKI敏感性。此外，具有最佳TKI缓解的患者中的残留CML细胞集中在ADAM 8+人群中。我们的研究表明，即使在TKI反应最佳的患者中，ADAM 8也是残留CML细胞的标志物，并将成为复发的预测因子和TKI耐药CML细胞的治疗靶点。我们建立了来源于CML-iPSCs的CML干细胞模型，ADAM 8被鉴定为TKI耐药CML细胞的抗原。抑制ADAM 8恢复了原代样品中的TKI敏感性。ADAM 8是具有最佳TKI应答的患者中残留CML细胞的标志物。CML干细胞的缺乏和异质性是分析的障碍。在我们的研究中，来自CML-iPSC的CML干细胞模型将ADAM 8鉴定为TKI抗性细胞的抗原。在CML患者中，ADAM 8+细胞显示TKI耐药，TKI治疗后残留的CML细胞集中在ADAM 8+细胞群中，表明ADAM 8是TKI耐药CML细胞的标志物。
Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells. We established a model of CML stem cells derived from CML-iPSCs ADAM8 is identified as an antigen of TKI-resistant CML cells The inhibition of ADAM8 restored TKI sensitivity in primary samples ADAM8 is a marker of residual CML cells in patients with optimal TKI response The paucity and heterogeneity of CML stem cells are obstacles for analyses. In our study, a model of CML stem cells derived from CML-iPSCs identified ADAM8 as an antigen of TKI-resistant cells. In CML patients, ADAM8+ cells showed TKI resistance and residual CML cells after TKIs-treatment were concentrated in ADAM8+ population, suggesting that ADAM8 is a marker of TKI-resistant CML cells.
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