在单细胞分辨率下解决npm1突变AML患者间和患者内部异质性

IF 13.4 1区 医学 Q1 HEMATOLOGY
E. Onur Karakaslar, Eva M. Argiro, Nadine E. Struckman, Ramin Shirali HZ, Jeppe F. Severens, M. Willy Honders, Susan L. Kloet, Hendrik Veelken, Marcel JT Reinders, Marieke Griffioen, Erik B. van den Akker
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引用次数: 0

摘要

npm1突变的AML是国际骨髓性肿瘤分类系统中最大的实体之一,该系统基于整合形态学和临床数据以及基因组数据。然而,先前的研究表明,基于大量转录组学的亚型可以改善预后和治疗指导。在这里,我们通过对16种AML进行单细胞rna测序和光谱流式细胞术来表征npm1突变AML的异质性,这些AML属于三种不同的亚型,之前通过大量转录组学鉴定。利用单细胞表达谱,我们生成了npm1突变的AML的综合图谱,共同重建了完整的骨髓形成。三种npm1突变的转录亚型在骨髓细胞簇的比例上表现出一致的差异,在谱系承诺和成熟停滞方面具有不同的模式。在所有样本中,在不同的骨髓细胞群中检测到白血病细胞,这表明npm1突变的AML严重偏斜,但在骨髓生成中并未完全停止。相同样本的多色光谱流式细胞术重现了这些扭曲模式,表明三种npm1突变亚型可以在不同的平台上一致地识别出来。此外,我们的分析强调了罕见造血干细胞丰度的差异,这表明在骨髓形成早期就发生了倾斜。总之,通过利用单细胞rna测序和光谱流式细胞术,我们详细描述了npm1突变AML中谱系倾斜的三种不同且可重复的模式,这些模式可能与npm1突变AML患者的预后和治疗具有潜在的相关性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution

Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution

NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas of NPM1-mutated AML, collectively reconstituting complete myelopoiesis. The three NPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, leukemic cells were detected across different myeloid cell clusters, indicating that NPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the three NPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing in NPM1-mutated AML that may have potential relevance for prognosis and treatment of patients with NPM1-mutated AML.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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