Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy
Advanced Science ( IF 14.3 ) Pub Date : 2023-06-04 , DOI: 10.1002/advs.202300445
Guanghao Liang _{1,

2} , Linchen Wang _{1,

2} , Qiancheng You _{3,

4} , Kirk Cahill ₅ , Chuanyuan Chen _{1,

2} , Wei Zhang _{6,

7} , Noreen Fulton _{5,

8} , Wendy Stock _{5,

8} , Olatoyosi Odenike _{5,

8} , Chuan He _{3,

4,

9} , Dali Han _{1,

2,

10}

Affiliation

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China.
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.
Howard Hughes Medical Institute, Chicago, IL, 60637, USA.
Section of Hematology/Oncology, Department of Medicine, University of Chicago Medicine, Chicago, IL, 60637, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Bristol-Myers Squibb, San Diego, CA, 92121, USA.
Comprehensive Cancer Center, University of Chicago Medicine, Chicago, IL, 60637, USA.
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.

Azacitidine (AZA) is a DNA methyltransferase inhibitor and epigenetic modulator that can be an effective agent in combination with chemotherapy for patients with high-risk acute myeloid leukemia (AML). However, biological factors driving the therapeutic response of such hypomethylating agent (HMA)-based therapies remain unknown. Herein, the transcriptome and/or genome-wide 5-hydroxymethylcytosine (5hmC) is characterized for 41 patients with high-risk AML from a phase 1 clinical trial treated with AZA epigenetic priming followed by high-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito). Digital cytometry reveals that responders have elevated Granulocyte-macrophage-progenitor-like (GMP-like) malignant cells displaying an active cell cycle program. Moreover, the enrichment of natural killer (NK) cells predicts a favorable outcome in patients receiving AZA-HiDAC-Mito therapy or other AZA-based therapies. Comparing 5hmC profiles before and after five-day treatment of AZA shows that AZA exposure induces dose-dependent 5hmC changes, in which the magnitude correlates with overall survival (p = 0.015). An extreme gradient boosting (XGBoost) machine learning model is developed to predict the treatment response based on 5hmC levels of 11 genes, achieving an area under the curve (AUC) of 0.860. These results suggest that cellular composition markedly impacts the treatment response, and showcase the prospect of 5hmC signatures in predicting the outcomes of HMA-based therapies in AML.

中文翻译：

细胞组成和5hmC特征预测AML患者对阿扎胞苷联合化疗的治疗反应

阿扎胞苷 (AZA) 是一种 DNA 甲基转移酶抑制剂和表观遗传调节剂，可与化疗联合治疗高危急性髓系白血病 (AML) 患者。然而，驱动此类基于低甲基化剂（HMA）的疗法的治疗反应的生物因素仍然未知。在此，对来自一项 1 期临床试验的 41 名高危 AML 患者的转录组和/或全基因组 5-羟甲基胞嘧啶 (5hmC) 进行了表征，这些患者接受 AZA 表观遗传启动，然后接受高剂量阿糖胞苷和米托蒽醌 (AZA-HiDAC-美图）。数字细胞计数显示，应答者的粒细胞-巨噬细胞祖细胞样（GMP 样）恶性细胞数量增加，显示出活跃的细胞周期程序。此外，自然杀伤 (NK) 细胞的富集预示着接受 AZA-HiDAC-Mito 疗法或其他基于 AZA 的疗法的患者会获得良好的结果。比较 AZA 治疗五天之前和之后的 5hmC 谱表明，AZA 暴露会引起剂量依赖性 5hmC 变化，其中变化幅度与总生存期相关 ( p = 0.015)。开发了极端梯度增强 (XGBoost) 机器学习模型，用于根据 11 个基因的 5hmC 水平预测治疗反应，曲线下面积 (AUC) 为 0.860。这些结果表明细胞组成显着影响治疗反应，并展示了 5hmC 特征在预测基于 HMA 的 AML 治疗结果方面的前景。

更新日期：2023-06-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南