Multi-Omic Analysis Reveals the Impact of Bortezomib in Hyperleukocytic Acute Myeloid Leukemia

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2024-11-25 DOI:10.1002/cam4.70438

Jinxian Wu, Xinqi Li, Bei Xiong, Wanyue Yin, Ruihang Li, Guopeng Chen, Linlu Ma, Xiqin Tong, Xiaoyan Liu, Fuling Zhou

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Abstract

Background

Hyperleukocytic acute myeloid leukemia (HL-AML) is associated with early complications and high mortality rates, highlighting the urgent need for more effective therapeutic strategies.

Methods

This study conducted label-free proteomic analysis on serum from HL-AML and non-HL AML (NHL-AML) patients, integrating the data with the OHSU transcriptomic database. Flow cytometry was used to evaluate the in vitro impact of bortezomib. The in vivo effectiveness of bortezomib was assessed using the patient-derived xenograft (PDX) model of HL-AML.

Results

Through integrated analysis of serum proteomics and transcriptomics, we observed an abnormal enrichment of the NF-kappa B pathway in HL-AML, suggesting its potential as a novel therapeutic target. Given that bortezomib is an inhibitor of the NF-kappa B pathway, HL-AML bone marrow cells were treated with varying concentrations of bortezomib (0, 5, 10, and 20 nM) in vitro. The results indicated a significant cytotoxic effect of bortezomib on HL-AML cells, accompanied by increased apoptosis rates and decreased proliferation. Co-administration of bortezomib with the frontline clinical chemotherapeutic regimen of daunorubicin and cytarabine (DA regimen) significantly extended mouse survival. Bone marrow immunophenotyping showed reductions in CD45⁺ and CD33⁺ cell populations, indicating disease amelioration. Immunohistochemical analysis further confirmed the inhibitory effect on the NF-kappa B pathway, as evidenced by reduced levels of P-IKBα and P-p65 proteins, validating the proposed therapeutic mechanism.

Conclusions

These data suggest that combination therapy involving bortezomib and the DA regimen may represent a promising strategy for HL-AML.

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多指标分析揭示硼替佐米对高白细胞急性髓性白血病的影响

背景高白细胞急性髓性白血病（HL-AML）与早期并发症和高死亡率有关，因此迫切需要更有效的治疗策略。本研究对HL-AML和非HL-AML（NHL-AML）患者的血清进行了无标记蛋白质组分析，并将数据与OHSU转录组数据库进行了整合。流式细胞术用于评估硼替佐米的体外影响。使用 HL-AML 患者衍生异种移植 (PDX) 模型评估硼替佐米的体内疗效。结果通过对血清蛋白质组学和转录组学的综合分析，我们观察到 NF-kappa B 通路在 HL-AML 中异常富集，这表明它有可能成为一个新的治疗靶点。鉴于硼替佐米是 NF-kappa B 通路的抑制剂，我们在体外用不同浓度的硼替佐米（0、5、10 和 20 nM）处理 HL-AML 骨髓细胞。结果表明，硼替佐米对 HL-AML 细胞有明显的细胞毒性作用，并伴随着细胞凋亡率的增加和增殖的减少。硼替佐米与临床一线化疗方案--多柔比星和阿糖胞苷（DA方案）联合用药可显著延长小鼠的存活时间。骨髓免疫分型显示，CD45+和CD33+细胞群减少，表明疾病有所改善。免疫组化分析进一步证实了对 NF-kappa B 通路的抑制作用，P-IKBα和 P-p65 蛋白水平的降低证明了这一点，验证了所提出的治疗机制。结论这些数据表明，硼替佐米和 DA 方案联合治疗 HL-AML 可能是一种很有前景的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.