Targeting DNMT1 by demethylating agent OR-2100 increases tyrosine kinase inhibitors-sensitivity and depletes leukemic stem cells in chronic myeloid leukemia
Targeting DNMT1 by demethylating agent OR-2100 increases tyrosine kinase inhibitors-sensitivity and depletes leukemic stem cells in chronic myeloid leukemia
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DOI：
10.1016/j.canlet.2021.11.032
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发表时间：
2022-02-01
期刊：
影响因子：
9.7
通讯作者：
Kimura, Shinya
中科院分区：
文献类型：
--
作者：
Kamachi, Kazuharu;Ureshino, Hiroshi;Kimura, Shinya
ABL 1酪氨酸激酶抑制剂（TKI）可显著改善慢性粒细胞白血病（CML）的预后，但10-20%的患者在TKI敏感性较低的情况下获得次优反应。此外，残留的白血病干细胞（LSC）参与TKI停药后的分子复发。异常的DNA超甲基化导致TKI敏感性降低和CML中LSC的持续存在。DNMT 1是造血干细胞的关键调节因子，这表明靶向DNMT 1的异常DNA超甲基化代表了CML的潜在治疗靶点。我们研究了地西他滨的第一个口服单一化合物前药OR-2100（OR 21）的疗效。OR 21作为单药治疗表现出抗肿瘤作用，在联合治疗中，它增加了TKI诱导的细胞凋亡和肿瘤抑制基因的诱导，包括CML细胞中编码SHP-1的PTPN 6。OR 21与伊马替尼组合显著抑制异种移植模型中的肿瘤生长。在BCR-ABL 1转导的小鼠模型中，OR 21和联合治疗降低了LSC的丰度并抑制了植入。这些结果表明，使用OR 21靶向DNMT 1发挥抗肿瘤作用并损害CML中的LSC。因此，TKI和OR 21的联合治疗代表了CML的一种有前景的治疗策略。
ABL1 tyrosine kinase inhibitors (TKIs) dramatically improve the prognosis of chronic myeloid leukemia (CML), but 10-20% of patients achieve suboptimal responses with low TKIs sensitivity. Furthermore, residual leukemic stem cells (LSCs) are involved in the molecular relapse after TKIs discontinuation. Aberrant DNA hypermethylation contributes to low TKIs sensitivity and the persistence of LSCs in CML. DNMT1 is a key regulator of hematopoietic stem cells, suggesting that aberrant DNA hypermethylation targeting DNMT1 represents a potential therapeutic target for CML. We investigated the efficacy of OR-2100 (OR21), the first orally available single-compound prodrug of decitabine. OR21 exhibited anti-tumor effects as a monotherapy, and in combination therapy it increased TKI-induced apoptosis and induction of tumor suppressor genes including PTPN6 encoding SHP-1 in CML cells. OR21 in combination with imatinib significantly suppressed tumor growth in a xenotransplant model. OR21 and combination therapy decreased the abundance of LSCs and inhibited engraftment in a BCR-ABL1-transduced mouse model. These results demonstrate that targeting DNMT1 using OR21 exerts anti-tumor effects and impairs LSCs in CML. Therefore, combination treatment of TKIs and OR21 represents a promising treatment strategy in CML.