title: Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects.
abstract: BACKGROUND
  Inosine triphosphate pyrophosphohydrolase (ITPase) is a 'house-cleaning' enzyme that degrades non-canonical ('rogue') nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects. Furthermore, we investigated whether accumulating mtDNA defects may then be a risk factor for cell transformation, in adult haematological malignancy (AHM).
  
  
  METHODS
  DNA was extracted from peripheral blood and bone marrow samples. Microarray-based sequencing of mtDNA was performed on 13 AHM patients confirmed as carrying the ITPA 94C>A mutation causing low ITPase activity, and 4 AHM patients with wildtype ITPA. The frequencies of ITPA 94C>A and IVS2+21A>C polymorphisms were studied from 85 available AHM patients.
  
  
  RESULTS
  ITPA 94C>A was associated with a significant increase in total heteroplasmic/homoplasmic mtDNA mutations (p<0.009) compared with wildtype ITPA, following exclusion of haplogroup variants. This suggested that low ITPase activity may induce mitochondrial abnormalities. Compared to the normal population, frequencies for the 94C>A and IVS2+21A>C mutant alleles among the AHM patients were higher for myelodyplastic syndrome (MDS) - but below significance; were approximately equivalent for chronic lymphoblastic leukemia; and were lower for acute myeloid leukemia.
  
  
  CONCLUSIONS
  This study invokes a new paradigm for the evolution of MDS, where nucleotide imbalances produced by defects in 'house-cleaning' genes may induce mitochondrial dysfunction, compromising cell integrity. It supports recent studies which point towards an important role for ITPase in cellular surveillance of rogue nucleotides.
authors.affiliation: King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Mazin A
authors.initials: MA
authors.lastname: Zamzami
authors.forename: John A
authors.initials: JA
authors.lastname: Duley
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Price
authors.forename: Deon J
authors.initials: DJ
authors.lastname: Venter
authors.forename: John W
authors.initials: JW
authors.lastname: Yarham
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Laurence P
authors.initials: LP
authors.lastname: Catley
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Florin
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.forename: Francis
authors.initials: F
authors.lastname: Bowling
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D004272:DNA, Mitochondrial; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase
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