A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML.

IF 11.5 Q1 HEMATOLOGY
Lanpeng Chen, Eline Pronk, Claire van Dijk, Yujie Bian, Jacqueline Feyen, Tim van Tienhoven, Meltem Yildirim, Paola Pisterzi, Madelon M E de Jong, Alejandro Bastidas, Remco M Hoogenboezem, Chiel Wevers, Eric M Bindels, Bob Löwenberg, Tom Cupedo, Mathijs A Sanders, Marc H G P Raaijmakers
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Abstract

Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPC) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors are predicted to repress high-output hematopoietic stem cell subsets in NPM1-mutated acute myeloid leukemia (AML), with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcomes after chemotherapy across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment.

Significance: Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcomes in human AML. See related commentary by Lisi-Vega and Méndez-Ferrer, p. 349. This article is featured in Selected Articles from This Issue, p. 337.

单细胞分类预测炎症小生境重塑以驱动人类AML的组织衰竭和结果。
癌症的起始是由肿瘤起始细胞与其基质/免疫环境之间的相互作用所协调的。在这里,通过适应的单细胞RNA测序,我们破译了组织驻留的造血干/祖细胞(HSPC)与其在人类骨髓中具有天然小生境的肿瘤对应物之间的预测信号。LEPR+基质细胞通过预测与骨髓中所有细胞的相互作用被鉴定为造血的中枢调节因子。在NPM1突变的急性髓系白血病(AML)中,炎症小生境重塑和由此导致的关键HSPC调节因子的剥夺被预测会抑制高输出造血干细胞亚群,并具有克隆细胞的相对抗性。反映生态位重塑的基质基因特征与所有遗传风险类别的化疗后复发率降低和良好结果相关。因此,定义人类AML的细胞间信号的阐明预测,干细胞小生境的炎症重塑驱动组织抑制和克隆选择,但在化疗治疗的背景下,可能对复发起始细胞造成脆弱性。意义:促肿瘤炎症被认为是肿瘤发生的一个有利特征,但其机制尚不完全清楚。通过破译组织驻留干细胞及其肿瘤对应物与其环境之间的预测信号,我们确定基质小生境的炎症重塑是人类AML正常组织抑制和临床结果的决定因素。见Lisi Vega和Méndez Ferrer的相关评论,第349页。这篇文章刊登在本期精选文章中,第337页。
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
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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