A three-dimensional ex vivo model recapitulates in vivo features and drug resistance phenotypes in childhood acute lymphoblastic leukemia

IF 13.4 1区 医学 Q1 HEMATOLOGY
Magdalini Kanari, Iria Jimenez Garcia, Fabio D. Steffen, Lisa A. Krattiger, Charles Bataclan, Wangjie Liu, Benjamin R. Simona, Bart Deplancke, Olaia Naveiras, Martin Ehrbar, Beat Bornhauser, Jean-Pierre Bourquin
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Abstract

Acute lymphoblastic leukemia (ALL) preferentially localizes in the bone marrow (BM) and displays recurrent patterns of medullary and extra-medullary involvement. Leukemic cells exploit their niche for propagation and survive selective pressure by chemotherapy in the BM microenvironment, suggesting the existence of protective mechanisms. Here, we established a three-dimensional (3D) BM mimic with human mesenchymal stromal cells and endothelial cells that resemble vasculature-like structures to explore the interdependence of leukemic cells with their microenvironment. This model recapitulates recurrent topologic differences between B-cell and T-cell precursor ALL, whereby B-ALL interacts more closely with the mesenchymal compartment. Migration versatility was found to be associated with subtype, consistent with increased motility observed in T-ALL in vivo. Single-cell RNA signatures revealed similarities to profiles from in vivo patient derived xenografts, suggesting relevant states ex vivo. Furthermore, enhanced migration, adherence and cell cycle heterogeneity was visualized in our co-culture model. Finally, drug response experiments in this 3D model confirm clinically relevant sensitivity and resistance patterns that reflect specific disease phenotypes and may provide a broader dynamic range for drug response testing.

Abstract Image

一个三维离体模型概括了儿童急性淋巴细胞白血病的体内特征和耐药表型
急性淋巴细胞白血病(ALL)优先定位于骨髓(BM),并表现出髓质和髓外累及的复发模式。白血病细胞利用其生态位进行繁殖,并在化疗的选择压力下在BM微环境中存活,表明存在保护机制。在这里,我们用类似血管样结构的人间充质基质细胞和内皮细胞建立了三维(3D)骨髓模拟,以探索白血病细胞与其微环境的相互依存关系。该模型概括了b细胞和t细胞前体ALL之间反复出现的拓扑差异,因此B-ALL与间质室更密切地相互作用。迁移多功能性被发现与亚型相关,与体内T-ALL观察到的运动性增加一致。单细胞RNA特征显示与体内患者来源的异种移植物相似,提示相关的体外状态。此外,在我们的共培养模型中,可以看到增强的迁移、粘附和细胞周期异质性。最后,该3D模型中的药物反应实验证实了临床相关的敏感性和耐药性模式,这些模式反映了特定的疾病表型,并可能为药物反应测试提供更广泛的动态范围。
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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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