Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Abstract

The mitochondrial respiratory chain (MRC) consists of protein complexes I, II, III, IV and V that support oxidative phosphorylation (OXPHOS), which depends on electron transport to generate adenosine triphosphate (ATP). Electron “leakage” from the MRC generates reactive oxygen species (ROS). Chronic myeloid leukemia in chronic phase (CML-CP) stem cells (LSCs) produce high levels of mitochondrial ROS, causing oxidative DNA damage, resulting in genomic instability, generating imatinib-resistant BCR–ABL1 kinase mutants and additional chromosomal aberrations. Using global mRNA microarray analysis combined with Ingenuity Pathway Analysis we found that LSCs display enhanced expression of genes encoding MRC complexes I, II, IV and V. However, expression of genes encoding complex III was deregulated. Treatment with imatinib did not correct the aberrant levels of MRC genes. Therefore we postulate that abnormal expression of MRC genes may facilitate electron “leakage” to promote the production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.

Keywords::

• CML leukemia stem cells
• oxidative phosphorylation
• microarray analysis

Acknowledgements

This work was supported in part by grants CA123014 and CA134458 to T. Skorski. D. Irvine is a Chief Scientist's Office Clinical Research Fellow; M. Copland is funded by the Scottish Funding Council (SCD/04) and Leukaemia and Lymphoma Research (No. 11017). Procurement of biospecimens was facilitated by the Glasgow Tissue Biorepository. This study was supported by the Glasgow Experimental Cancer Medicine Centre (ECMC), which is funded by Cancer Research UK and the Chief Scientist's Office (Scotland).

Potential conflict of interest

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