Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected.

IF 2.5 4区 医学 Q3 GENETICS & HEREDITY
Mutagenesis Pub Date : 2021-11-29 DOI:10.1093/mutage/geab033
Liana E Gynn, Elizabeth Anderson, Gareth Robinson, Sarah A Wexler, Gillian Upstill-Goddard, Christine Cox, Jennifer E May
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引用次数: 7

Abstract

Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

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与白血病HL-60细胞共培养的原代间充质间质细胞对阿糖胞苷诱导的遗传毒性敏感,而白血病细胞则受到保护。
肿瘤微环境是许多癌症类型的特征。在血液系统恶性肿瘤中,骨髓间充质间质细胞(MSC)保护恶性细胞免受药物诱导的细胞毒性。然而,对恶性肿瘤对支持基质的影响知之甚少。值得注意的是,尚不清楚这些相互作用是否会改变长期的遗传毒性损害。核苷类似物阿糖胞苷(ara-C),常见于血液学治疗,仍然是急性髓性白血病最有效的药物,但三分之一的患者产生耐药性。本研究旨在评价间充质干细胞与恶性细胞共培养对ara-C遗传毒性调节的双向作用。在用生理剂量的ara-C治疗之前,用跨孔插入物将从患者骨髓抽吸物中分离出来用于血液学研究的原代MSC与恶性造血细胞(白血病HL-60)共培养。通过微核和碱性彗星试验评估共培养基因毒性效应。与未接受化疗的患者相比,接受化疗的患者BM细胞的体外存活率降低(P = 0.0049),遗传毒性增加(P = 0.3172)。研究首次表明,MSC可以保护HL-60免受ara- c诱导的遗传毒性,与单一培养相比,共培养的MN发生率降低(P = 0.0068)。受HL-60影响的ara- c处理的MSC中,彗尾强度也显著增加(P = 0.0308)。与HL60共培养后,MSC对ara-C遗传毒性也表现出致敏性(P = 0.0116),当MSC- hl -60共培养物暴露于ara-C时,显示出更大的致敏性(P = 0.0409)。本研究首次表明恶性HSC和MSC双向调节遗传毒性,为未来研究确定白血病微环境中遗传毒性改变的机制提供了基础。骨髓间充质干细胞在化疗暴露后保留长期的遗传毒性和功能损伤。了解造成这种损伤的相互作用可以为减少治疗相关并发症(如继发性恶性肿瘤和骨髓衰竭)提供信息。
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
Mutagenesis
Mutagenesis 生物-毒理学
CiteScore
5.90
自引率
3.70%
发文量
22
审稿时长
6-12 weeks
期刊介绍: Mutagenesis is an international multi-disciplinary journal designed to bring together research aimed at the identification, characterization and elucidation of the mechanisms of action of physical, chemical and biological agents capable of producing genetic change in living organisms and the study of the consequences of such changes.
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