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Open Access 01-12-2013 | Research

Inosine Triphosphate Pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects

Authors: Mazin A Zamzami, John A Duley, Gareth R Price, Deon J Venter, John W Yarham, Robert W Taylor, Laurence P Catley, Timothy HJ Florin, Anthony M Marinaki, Francis Bowling

Published in: Journal of Hematology & Oncology | Issue 1/2013

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.

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Title: Inosine Triphosphate Pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects
Authors: Mazin A Zamzami
John A Duley
Gareth R Price
Deon J Venter
John W Yarham
Robert W Taylor
Laurence P Catley
Timothy HJ Florin
Anthony M Marinaki
Francis Bowling
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/1756-8722-6-24

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