大规模筛选鉴定19基因MitoScore以改善急性髓性白血病的风险评估

IF 4.5 3区生物学 Q2 CELL BIOLOGY

Mitochondrion Pub Date : 2025-02-19 DOI:10.1016/j.mito.2025.102011

Liting Niu , Hanfei Guo , Yijing Zhao

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引用次数: 0

摘要

daml表现出大量的分子和遗传异质性。因此，确定参与发病机制的关键生物学过程和相关基因，以及对治疗耐药的贡献，对于提高临床疗效至关重要。然而，对AML中线粒体功能的评估已逐渐得到承认，但尚未得到广泛重视。因此，优先鉴定线粒体相关的生物标志物对于增强现有的分层方法和指导风险适应疗法的决策至关重要。方法系统整合和分析9个在线AML转录组学测序数据库数据，筛选Human.MitoCarta3.0线粒体基因数据库，鉴定AML特异性线粒体基因。使用LASSO回归分析在HOVON数据库中建立预后线粒体评分作为训练队列（n = 618），并在另外8个公开的独立队列（n = 1,697）中进行验证。结果进一步生成了2315例AML患者的线粒体功能基因m19评分，并显示出较高的预后能力，命名为MitoScore。MitoScore是一种独立的生存预后生物标志物(p <；0.001)。MitoScore有效地区分了几种遗传异常，并显著改善了ELN（欧洲白血病网）分类。MitoScore高的患者对诱导化疗和相关难治性AML的反应明显较差(p <；0.001)。在有利风险基因变异和细胞遗传学异常组中，MitoScore明显低于无这些变异的患者。相反，在不良组中，MitoScore明显高于有利遗传异常患者。结论：我们的研究结果强调了MitoScore作为精细风险分层和预测化疗耐药的有力工具的实用性。

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Large-scale screens identify a 19-Gene MitoScore for improved risk assessment in acute myeloid leukemia

Background

AML exhibits substantial molecular and genetic heterogeneity. Therefore, identifying key biological processes and related genes involved in the pathogenesis, as well as contributing to therapeutic resistance, is imperative for enhancing clinical outcomes. However, the assessment of mitochondrial function in AML has gradually been acknowledged but has not been widely emphasized. Hence, prioritizing the identification of mitochondrial-related biomarkers is crucial to enhance existing stratification methodologies and guide decisions on risk-adapted therapies.

Methods

We systematically integrated and analyzed data from nine online AML transcriptomics sequencing databases, screening the Human.MitoCarta3.0 mitochondrial gene database to identify AML-specific mitochondrial genes. A prognostic mitochondrial score was developed using LASSO regression analysis in the HOVON database as training cohort (n = 618) and validated in another eight publicly available independent cohorts (n = 1,697).

Results

A 19-mitochondrial function gene AML score was further generated and exhibited high prognostic power in 2,315 AML patients, named as MitoScore. MitoScore was an independent survival prognosis biomarker (p < 0.001). The MitoScore effectively distinguishes several genetic abnormalities and significantly improves the ELN (European Leukemia Net) classification. Patients with a high MitoScore demonstrated a notably poor response to induction chemotherapy and related refractory AML (p < 0.001). In the favorable risk gene variant and cytogenetic abnormality group, MitoScore was significantly lower compared to patients without those variants. Conversely, in the adverse group, MitoScore was significantly higher compared to patients with favorable genetic abnormalities.

Conclusions

Our findings underscore the utility of the MitoScore as a powerful tool for refined risk stratification and predicting chemotherapy resistance.

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来源期刊

Mitochondrion 生物-细胞生物学

CiteScore

9.40

自引率

4.50%

发文量

审稿时长

13.6 weeks

期刊介绍： Mitochondrion is a definitive, high profile, peer-reviewed international research journal. The scope of Mitochondrion is broad, reporting on basic science of mitochondria from all organisms and from basic research to pathology and clinical aspects of mitochondrial diseases. The journal welcomes original contributions from investigators working in diverse sub-disciplines such as evolution, biophysics, biochemistry, molecular and cell biology, genetics, pharmacology, toxicology, forensic science, programmed cell death, aging, cancer and clinical features of mitochondrial diseases.