Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis.
Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis.
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DOI：
10.1038/s41598-022-15520-z
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发表时间：
2022-07-05
影响因子：
4.6
通讯作者：
Visnjic, Dora
中科院分区：
文献类型：
--
作者：
Tomic, Barbara;Smoljo, Tomislav;Lalic, Hrvoje;Dembitz, Vilma;Batinic, Josip;Batinic, Drago;Bedalov, Antonio;Visnjic, Dora
急性髓性白血病（AML）的特点是分化受阻，使分化治疗成为一种很有前途的治疗策略。最近对异柠檬酸脱氢酶（IDH）抑制剂的成功研究激发了人们对AML分化治疗的兴趣，因此一些新药被提出，包括二氢乙酸脱氢酶（DHODH）抑制剂，一种嘧啶合成酶。阿糖胞苷是标准AML治疗的骨干，已知在低剂量下诱导分化，但其机制尚未完全阐明。我们之前报道过5-氨基咪唑-4-羧基酰胺核糖核苷（AICAr）和brequinar（一种DHODH抑制剂）通过嘧啶耗竭激活失调性毛细血管扩张和rad3相关(ATR)/检查点激酶1 (Chk1)，诱导髓性白血病分化。在这项研究中，我们使用免疫印迹、流式细胞术分析、药物抑制剂和基因失活的Chk1在髓系白血病细胞系中，我们发现低剂量阿糖胞苷通过激活Chk1诱导分化。此外，阿糖胞苷在对AICAr和DHODH抑制剂敏感的原发性AML样本亚群中诱导体外分化。我们的研究结果表明，低剂量阿糖胞苷刺激白血病细胞分化依赖于Chk1的激活，因此与嘧啶合成抑制剂具有相同的途径。
Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors.
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影响因子：
3.8
作者：
Dembitz V;Lalic H;Kodvanj I;Tomic B;Batinic J;Dubravcic K;Batinic D;Bedalov A;Visnjic D
通讯作者：
Visnjic D
影响因子：
11.4
作者：
Christian, Sven;Merz, Claudia;Janzer, Andreas
通讯作者：
Janzer, Andreas
影响因子：
20.3
作者：
Sanz, Miguel A.;Fenaux, Pierre;Lo-Coco, Francesco
通讯作者：
Lo-Coco, Francesco
影响因子：
4.8
作者：
Fernandes, Norvin D.;Sun, Yingli;Price, Brendan D.
通讯作者：
Price, Brendan D.
影响因子：
2.6
作者：
Lalic, Hrvoje;Dembitz, Vilma;Visnjic, Dora
通讯作者：
Visnjic, Dora