We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
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.
- Authors
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.
- Subjects
ACUTE myeloid leukemia; MYELODYSPLASTIC syndromes; BONE marrow diseases; STEM cell transplantation; DYSPLASIA; GENETIC polymorphisms; OXIDOREDUCTASES
- Publication
British Journal of Haematology, 2004, Vol 126, Issue 1, p63
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/j.1365-2141.2004.05006.x