Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS

Fern, Lorna; Pallis, Monica; Carter, G. Ian; Seedhouse, Claire; Russell, Nigel; Byrne, Jennifer

Abstract

The molecular pathogenesis of therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t-AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH-quinone oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non-myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0·001), particularly in those with clonal haemopoiesis (P < 0·002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P < 0·001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1·16–42·6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t-AML in NQO1-187Ser null individuals.

Citation

Fern, L., Pallis, M., Carter, G. I., Seedhouse, C., Russell, N., & Byrne, J. (2004). Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS. British Journal of Haematology, 126(1), 63-71. https://doi.org/10.1111/j.1365-2141.2004.05006.x

• Journal Article Type: Article
• Acceptance Date: Apr 6, 2024
• Online Publication Date: May 20, 2004
• Publication Date: 2004-07
• Deposit Date: Apr 5, 2024
• Journal: British Journal of Haematology
• Print ISSN: 0007-1048
• Electronic ISSN: 1365-2141
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 126
• Issue: 1
• Pages: 63-71
• DOI: https://doi.org/10.1111/j.1365-2141.2004.05006.x
• Public URL: https://nottingham-repository.worktribe.com/output/32755113
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05006.x