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.
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.
authors.affiliation: Division of Haematology, School of Clinical Laboratory Sciences, University of Nottingham, and Nottingham City Hospital, Nottingham, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Fern
authors.forename: Monica
authors.initials: M
authors.lastname: Pallis
authors.forename: G
authors.initials: G
authors.lastname: Ian Carter
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.forename: Nigel
authors.initials: N
authors.lastname: Russell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Byrne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002999:Clone Cells; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis; D006689:Hodgkin Disease / Q000601:surgery; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000601:surgery; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D011110:Polymorphism, Genetic; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D016615:Telomere / Q000648:ultrastructure*
chemical_list: D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human