Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Dec;43(4):1385-1399.
doi: 10.1007/s10555-024-10203-9. Epub 2024 Aug 5.

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

Caleb B Lill  1   2 , Stephen Fitter  1   2 , Andrew C W Zannettino  1   2 , Kate Vandyke  1   2 , Jacqueline E Noll  3   4
Affiliations
Review

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

Caleb B Lill et al. Cancer Metastasis Rev. 2024 Dec.

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.

Keywords: Acute lymphoblastic leukaemia; Adipocytes; Chemoresistance; Mesenchymal stromal cells; Microenvironment.

PubMed Disclaimer

Conflict of interest statement

Declarations Ethics approval Not applicable. Consent for publication All authors have read and approved the final version of the manuscript and consent to publication. Competing interests The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Integrin-mediated signalling promotes B-ALL chemoresistance. α4β1-VCAM-1 ligation induces expression of pro-survival signalling molecules via NF-κB activation and modulates mTOR activity via the MAPK/ERK signalling pathway to reduce B-ALL glucocorticoid sensitivity. Complexes composed of integrin β1, CXCR4 and hERG reduce activity of apoptosis-promoting proteins via ILK/PI3K/AKT signalling. VCAM-1, vascular cell adhesion molecule-1; FAK, focal adhesion kinase; MAPKK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; CXCR4, CXC-motif chemokine receptor type 4; hERG, human ether-a-go-go-related gene; PI3K, phosphoinositide 3-kinase; BAD, beclin-2-associated death promoter protein; GC, glucocorticoid
Fig. 2
Fig. 2
BM-MSCs supplement asparagine to overcome ASNase treatment cytotoxicity. Interactions with BM-MSC promote glutamine production and secretion by B-ALL blasts, which is subsequently converted to asparagine by ASNS and exported from BM-MSC via SNAT5, thereby reducing ASNase treatment effectiveness. SNAT5, sodium-coupled neutral amino acid transporter 5; ASCT2, alanine serine cysteine transporter 2; ASNS, asparagine synthetase; Asn, asparagine; Glu, glutamate; Gln, glutamine; Asp, aspartate; GS, glutamine synthetase
Fig. 3
Fig. 3
Adipocyte/B-ALL interactions contribute to B-ALL chemoresistance. B-ALL-secreted TNFα promotes secretion of lipids by adipocytes, which are used in fatty acid oxidation and decrease sensitivity to chemotherapeutics. Induction of the Nrf2-mediated oxidative stress pathway increases expression of the ROS scavenger, glutathione, thereby attenuating the effectiveness of therapeutics whose activity relies upon generating ROS (e.g. anthracyclines). Aldo-kedo reductases similarly reduce B-ALL anthracycline resistance by catalysing the formation of less cytotoxic derivatives such as daunorubicinol. ROS, reactive oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; GSS, glutathione synthetase; GCL, glutathione cysteine ligase; AKR, aldo–keto reductase; TNFα, tumour necrosis factor α
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. National Cancer Institute, DCCPS, Surveillance Research Program. (2020). Surveillance, Epidemiology, and End Results Program: SEER Cancer Stat Facts: Childhood leukemia (ages 0–19). https://seer.cancer.gov/statfacts/html/childleuk.html. Accessed 14 Feb 2024.
    1. Bhojwani, D., & Pui, C.-H. (2013). Relapsed childhood acute lymphoblastic leukaemia. The Lancet Oncology,14(6), e205–e217. 10.1016/S1470-2045(12)70580-6 - PubMed
    1. Terwilliger, T., & Abdul-Hay, M. (2017). Acute lymphoblastic leukemia: A comprehensive review and 2017 update. Blood Cancer Journal,7(6), e577–e577. 10.1038/bcj.2017.53 - PMC - PubMed
    1. Sun, W., Malvar, J., Sposto, R., Verma, A., Wilkes, J. J., Dennis, R., et al. (2018). Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: A therapeutic advances in childhood leukemia & lymphoma study. Leukemia,32(11), 2316–2325. 10.1038/s41375-018-0094-0 - PMC - PubMed
    1. Pui, C. H., Carroll, W. L., Meshinchi, S., & Arceci, R. J. (2011). Biology, risk stratification, and therapy of pediatric acute leukemias: An update. Journal of Clinical Oncology,29(5), 551–565. 10.1200/jco.2010.30.7405 - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources