title: Mitochondrial D-loop polymorphisms and mitochondrial DNA content in childhood acute lymphoblastic leukemia.
abstract: The mitochondrial displacement loop (D-loop) controls mitochondrial expression, with mutations and mitochondrial DNA (mtDNA) content linked to oncogenesis. We investigated D-loop polymorphisms and mtDNA content in childhood acute lymphoblastic leukemia (ALL). The D-loop was sequenced in 251 children: precursor B ALL (n=114), with 76 paired remission/relapse samples; T-ALL (n=24); cord blood controls (n=113). The mtDNA copy number was analyzed using real-time quantitative polymerase chain reaction for 92 controls and 54 ALL patients at diagnosis and remission. Polymorphisms around H-strand replication origin (nucleotides 150 to 199) and conserved sequence block II (nucleotides 299 to 317) were associated with leukemia biology and treatment response. T-ALL patients were more likely to have longer nt303 poly-C tract. T199C polymorphism was associated with increased risk of ALL in Malays; T152C was more frequent in good responders. There was no difference in mtDNA content between diagnostic ALL samples and controls; however, there was significant decrease in mtDNA content after treatment, especially in samples with OH polymorphisms. Somatic mutations were found in 13% (9 of 76) of patients, suggesting a link to leukemogenesis. Our results suggest that polymorphisms impacting transcriptional control could affect mtDNA replication. Decrease in mtDNA content after treatment may confer susceptibility to chemotherapy and be a clue to the good prognosis of childhood ALL.
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Cecilia Sze-Nga
authors.initials: CS
authors.lastname: Kwok
authors.forename: Thuan Chong
authors.initials: TC
authors.lastname: Quah
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
authors.forename: Stacey Kiat-Hong
authors.initials: SK
authors.lastname: Tay
authors.forename: Allen Eng-Juh
authors.initials: AE
authors.lastname: Yeoh
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000008:administration & dosage; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004272:DNA, Mitochondrial / Q000235:genetics*; D003630:Daunorubicin / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005312:Fetal Blood; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D012074:Remission Induction; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D004272:DNA, Mitochondrial; D014750:Vincristine; D003907:Dexamethasone; D001215:Asparaginase; D003630:Daunorubicin