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

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-A...

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Bibliographic Details
Published in:Cancer and metastasis reviews 2024-12, Vol.43 (4), p.1385-1399
Main Authors: Lill, Caleb B., Fitter, Stephen, Zannettino, Andrew C. W., Vandyke, Kate, Noll, Jacqueline E.
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
Adipocytes
Adipocytes - metabolism
Adipocytes - pathology
Animals
Anthracycline
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Asparagine
Biomedical and Life Sciences
Biomedicine
Bone marrow
Cancer Research
Chemoresistance
Chemotherapy
Child
Drug Resistance, Neoplasm
Humans
Leukemia
Medical prognosis
Mesenchymal stem cells
Mesenchymal Stem Cells - metabolism
Mesenchymal Stem Cells - pathology
Microenvironments
Molecular modelling
Oncology
Pediatrics
Phenotypes
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Review
Stem cells
Tumor Microenvironment
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Summary: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.
ISSN:0167-7659
1573-7233
1573-7233
DOI:10.1007/s10555-024-10203-9