Molecular and cellular mechanisms of chemoresistance in paediatric pre-B cell acute lymphoblastic leukaemia.

IF 7.7 2区医学 Q1 ONCOLOGY Cancer and Metastasis Reviews Pub Date : 2024-12-01 Epub Date: 2024-08-05 DOI:10.1007/s10555-024-10203-9

Caleb B Lill, Stephen Fitter, Andrew C W Zannettino, Kate Vandyke, Jacqueline E Noll

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Abstract

Paediatric patients with relapsed B cell acute lymphoblastic leukaemia (B-ALL) have poor prognosis, as relapse-causing clones are often refractory to common chemotherapeutics. While the molecular mechanisms leading to chemoresistance are varied, significant evidence suggests interactions between B-ALL blasts and cells within the bone marrow microenvironment modulate chemotherapy sensitivity. Importantly, bone marrow mesenchymal stem cells (BM-MSCs) and BM adipocytes are known to support B-ALL cells through multiple distinct molecular mechanisms. This review discusses the contribution of integrin-mediated B-ALL/BM-MSC signalling and asparagine supplementation in B-ALL chemoresistance. In addition, the role of adipocytes in sequestering anthracyclines and generating a BM niche favourable for B-ALL survival is explored. Furthermore, this review discusses the role of BM-MSCs and adipocytes in promoting a quiescent and chemoresistant B-ALL phenotype. Novel treatments which target these mechanisms are discussed herein, and are needed to improve dismal outcomes in patients with relapsed/refractory disease.

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小儿前 B 细胞急性淋巴细胞白血病化疗抗药性的分子和细胞机制。

复发的 B 细胞急性淋巴细胞白血病（B-ALL）儿科患者预后较差，因为导致复发的克隆往往对普通化疗药具有耐药性。虽然导致化疗耐药性的分子机制多种多样，但有重要证据表明，B-ALL 病灶和骨髓微环境中的细胞之间的相互作用会调节化疗的敏感性。重要的是，已知骨髓间充质干细胞（BM-MSCs）和骨髓脂肪细胞通过多种不同的分子机制支持B-ALL细胞。本综述讨论了整合素介导的B-ALL/BM-间充质干细胞信号传导和天冬酰胺补充在B-ALL化疗耐药中的作用。此外，还探讨了脂肪细胞在封闭蒽环类药物和生成有利于 B-ALL 存活的 BM 龛中的作用。此外，本综述还讨论了 BM 间充质干细胞和脂肪细胞在促进静止和化疗耐药 B-ALL 表型中的作用。本文讨论了针对这些机制的新疗法，这些新疗法是改善复发/难治性疾病患者令人沮丧的预后所必需的。

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来源期刊

Cancer and Metastasis Reviews 医学-肿瘤学

CiteScore

17.00

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Contemporary biomedical research is on the threshold of an era in which physiological and pathological processes can be analyzed in increasingly precise and mechanistic terms.The transformation of biology from a largely descriptive, phenomenological discipline to one in which the regulatory principles can be understood and manipulated with predictability brings a new dimension to the study of cancer and the search for effective therapeutic modalities for this disease. Cancer and Metastasis Reviews provides a forum for critical review and discussion of these challenging developments. A major function of the journal is to review some of the more important and interesting recent developments in the biology and treatment of malignant disease, as well as to highlight new and promising directions, be they technological or conceptual. Contributors are encouraged to review their personal work and be speculative.