MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway.
MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway.
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MAP4K1 通过调节 DNA 损伤/修复系统和 MAPK 通路充当 AML 的肿瘤启动子和药物介体
DOI：
10.1016/j.ebiom.2021.103441
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发表时间：
2021-07
期刊：
影响因子：
11.1
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Ling Q;Li F;Zhang X;Mao S;Lin X;Pan J;Ye W;Wei W;Qian Y;Hu C;Huang X;Wang J;Wang H;Huang J;Wang Y;Jin J
背景：急性髓系白血病（acute myeloid leukemia，AML）是一组预后不良的异质性血液系统恶性肿瘤。确定有效治疗AML的生物标志物非常重要。激酶参与AML中的许多调节途径和生物活性。先前的研究表明，MAP 4K 1是一种丝氨酸/苏氨酸激酶，与免疫调节和癌症进展相关。然而，其在急性髓细胞白血病（AML）中的作用和机制尚未得到探讨。方法：对高三尖杉酯碱（HHT）耐药和高三尖杉酯碱（HHT）敏感细胞系进行RNA-seq分析。生物信息学工具用于差异分析。采用细胞培养和转染、细胞增殖、细胞凋亡和细胞周期测定、定量RT-PCR和Western blotting分析来探索体外生物学表型。结果：我们发现MAP 4K 1在HHT诱导的耐药AML细胞系中高度表达。此外，MAP 4K 1在AML细胞中的过表达诱导AML细胞对HHT的抗性。不仅如此，这项研究的结果表明，MAP 4K 1的过度表达是预测AML预后不良的独立危险因素。体外研究表明，MAP 4K 1通过MAPK和DNA损伤/修复途径调控细胞周期。因此，MAP 4K 1是开发AML疗法的潜在靶点。解释：这项研究表明，MAP 4K 1不仅调节HHT耐药性，而且还独立预测AML预后。此外，了解MAP 4K 1的调节机制揭示了耐药和难治性AML的新治疗策略。资金来源：本工作得到了国家自然科学基金（81800199、81670124、82070118）和浙江省自然科学基金（LY 20 H 080008）的资助。
Background: Acute myeloid leukemia (AML) is a group of heterogeneous hematologic malignancies correlates with poor prognosis. It is important to identify biomarkers for effective treatment of AML. Kinases participate in many regulatory pathways and biological activities in AML. Previous studies demonstrated that MAP4K1, a serine/threonine kinase, was associated with immune regulation and cancer progression. However, its role and mechanism in acute myeloid leukemia (AML) have not been explored. Methods: RNA-seq profiling was performed for Homoharringtonine (HHT)-resistant and Homoharringtonine (HHT)-sensitive cell lines. Bioinformatic tools were used for differential analysis. Cell culture and transfection, Cell proliferation, apoptosis and Cell cycle assay, Quantitative RT-PCR, and Western blotting analysis were used to explore biological phenotypes in vitro. Findings: We found that MAP4K1 was highly expressed in HHT-induced resistant AML cell lines. In addition, overexpression of MAP4K1 in AML cells induced resistance of AML cells against HHT. Not only that, the findings of this study showed that overexpression of MAP4K1 was an independent risk factor that predicts poor prognosis of AML. Further, In vitro studies showed that MAP4K1 modulated cell cycle through MAPK and DNA damage/repair pathways. Therefore, MAP4K1 is a potential target for developing therapies for AML. Interpretation: This study demonstrates that MAP4K1 not only regulates HHT resistance but also independently predicts AML prognosis. In addition, understanding the regulatory mechanism of MAP4K1 reveals novel treatment strategies for resistant and refractory AML. Fundings: This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No.81800199, 81670124, 82070118) and the Natural Science Foundation of Zhejiang Province (LY20H080008).
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
11.4
作者：
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通讯作者：
Iscove, NN
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
Fragkos, Michalis;Jurvansuu, Jaana;Beard, Peter
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影响因子：
3.4
作者：
Wang J;Song L;Yang S;Zhang W;Lu P;Li S;Li H;Wang L
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