Distinct stromal cell populations define the B-cell acute lymphoblastic leukemia microenvironment

IF 13.4 1区 医学 Q1 HEMATOLOGY
Mauricio N. Ferrao Blanco, Bexultan Kazybay, Mirjam Belderbos, Olaf Heidenreich, Hermann Josef Vormoor
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Abstract

The bone marrow microenvironment plays a critical role in B-cell acute lymphoblastic leukemia (B-ALL) progression, yet its cellular heterogeneity remains poorly understood. Using single-cell RNA sequencing on patient-derived bone marrow aspirates from pediatric B-ALL patients, we identified two distinct mesenchymal stromal cell (MSC) populations: early mesenchymal progenitors and adipogenic progenitors. Spatial transcriptomic analysis further revealed the localization of these cell types and identified a third stromal population, osteogenic-lineage cells, exclusively present in the bone biopsy. Functional ex vivo assays using sorted stromal populations derived from B-ALL patient bone marrow aspirates demonstrated that both early mesenchymal and adipogenic progenitors secrete key niche-supportive factors, including CXCL12 and Osteopontin, and support leukemic cell survival and chemoresistance. Transcriptomic profiling revealed that B-ALL cells interact differently with stromal subtypes. Notably, adipogenic progenitors, but not early mesenchymal progenitors, provide support to leukemic cells through interleukin-7 and VCAM1 signaling. Stromal cells from B-ALL patients exhibited an enhanced adipogenic differentiation capacity compared to healthy controls. Moreover, co-culture experiments showed that B-ALL cells induce adipogenic differentiation in healthy MSCs through a cell contact-dependent mechanism. Adipogenic progenitors were also enriched in relapse samples, implicating them in disease progression. These findings highlight the complexity of the B-ALL microenvironment and identify different specialized stromal niches with which the leukemic cells can engage.

Abstract Image

不同的基质细胞群定义了b细胞急性淋巴细胞白血病微环境
骨髓微环境在b细胞急性淋巴细胞白血病(B-ALL)的进展中起着关键作用,但其细胞异质性尚不清楚。通过对儿童B-ALL患者骨髓抽取物进行单细胞RNA测序,我们确定了两种不同的间充质间质细胞(MSC)群体:早期间充质祖细胞和脂肪祖细胞。空间转录组学分析进一步揭示了这些细胞类型的定位,并确定了第三种基质群体,成骨谱系细胞,只存在于骨活检中。从B-ALL患者骨髓抽吸中提取的基质群进行的功能性离体实验表明,早期间充质祖细胞和脂肪祖细胞都能分泌关键的生态位支持因子,包括CXCL12和骨桥蛋白,并支持白血病细胞存活和化疗耐药。转录组学分析显示B-ALL细胞与基质亚型的相互作用不同。值得注意的是,脂肪源性祖细胞,而不是早期间充质祖细胞,通过白细胞介素-7和VCAM1信号传导为白血病细胞提供支持。与健康对照相比,B-ALL患者的基质细胞表现出增强的成脂分化能力。此外,共培养实验表明,B-ALL细胞通过细胞接触依赖机制诱导健康间充质干细胞的成脂分化。脂肪源性祖细胞也在复发样本中富集,暗示它们与疾病进展有关。这些发现突出了B-ALL微环境的复杂性,并确定了白血病细胞可以参与的不同特化基质壁龛。
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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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