5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.
5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.
复制标题
DOI：
10.1186/s12885-020-07533-6
复制
发表时间：
2020-11-11
期刊：
影响因子：
3.8
通讯作者：
Visnjic D
中科院分区：
文献类型：
--
作者：
Dembitz V;Lalic H;Kodvanj I;Tomic B;Batinic J;Dubravcic K;Batinic D;Bedalov A;Visnjic D
全反式维甲酸（ATRA）为基础的治疗急性早幼粒细胞白血病（APL）是最成功的药物治疗急性髓细胞白血病（AML）。突变型异柠檬酸脱氢酶和二氢乳清酸脱氢酶（DHODH）抑制剂的最新发展重新引起了人们对非APL AML分化治疗的兴趣。我们以前的研究表明，5-氨基咪唑-4-甲酰胺核苷（AICAR）诱导分化的单核细胞系通过激活ATR/Chk 1通过嘧啶耗尽。在本研究中，AICAR对从非APL AML患者骨髓中分离的原代AML母细胞的活力和分化的影响进行了测试，并与DHODH抑制剂布喹那和ATRA的影响进行了比较。从35名患者获得骨髓样品，并离体培养白血病母细胞。MTT法检测细胞活力，流式细胞仪和形态学分析检测AML细胞分化。RNA测序和部分数据分析使用QuantiterProfiler软件包进行。使用GraphPad Prism 6.0进行统计分析。AICAR能够触发体外培养的对ATRA具有抗性的骨髓母细胞样品的分化。AICAR诱导的分化与增殖和对DHODH抑制的敏感性相关。在原代AML原始细胞中获得的RNA-seq数据证实，AICAR治疗诱导嘧啶代谢途径的下调以及涉及造血细胞谱系的基因集的上调。AICAR诱导原代非APL AML母细胞亚群的分化，这些作用与对众所周知的强效DHODH抑制剂的敏感性相关。补充信息随附于10.1186/s12885-020-07533-6。
All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA. Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0. AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage. AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor. Supplementary information accompanies this paper at 10.1186/s12885-020-07533-6.
登录
查看更多内容
影响因子：
168.9
作者：
Short, Nicholas J.;Rytting, Michael E.;Cortes, Jorge E.
通讯作者：
Cortes, Jorge E.
影响因子：
64.5
作者：
Narkar VA;Downes M;Yu RT;Embler E;Wang YX;Banayo E;Mihaylova MM;Nelson MC;Zou Y;Juguilon H;Kang H;Shaw RJ;Evans RM
通讯作者：
Evans RM
DOI：
10.1084/jem.20151574
发表时间：
2016-06-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pikman Y;Puissant A;Alexe G;Furman A;Chen LM;Frumm SM;Ross L;Fenouille N;Bassil CF;Lewis CA;Ramos A;Gould J;Stone RM;DeAngelo DJ;Galinsky I;Clish CB;Kung AL;Hemann MT;Vander Heiden MG;Banerji V;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
11.4
作者：
Christian, Sven;Merz, Claudia;Janzer, Andreas
通讯作者：
Janzer, Andreas
影响因子：
2.1
作者：
Dembitz, Vilma;Lalic, Hrvoje;Visnjic, Dora
通讯作者：
Visnjic, Dora