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

Abstract

Mitochondrial respiratory chain (MRC) consists of the protein complexes I, II, III, IV, and V to carry oxidative phosphorylation (OXPHOS), which depends on electron transport to generate ATP. Electron "leakage" from 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 imatinibresistant 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 production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.

ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

“…In embryonic, neural, normal, and tumoral breast tissues, stem/progenitor cells contain lower level of reactive oxygen species than their more mature progeny, sustaining their relative resistance to radiation (40,41). In leukemia, oxidative phosphorylation triggers genomic instability and is a putative mechanism explaining relapse after tyrosine kinase inhibitor treatment (42,43). Noteworthy, aldehyde dehydrogenase, a hallmark of embryonic, normal adult tissue and CSCs, oxidizes aldehydes to the corresponding carboxylic acids (44).…”

Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia

“…The greater prevalence of genetic instability in leukemic cells of patients with advanced disease arises from enhanced DNA damage and reduced capacity to repair that damage. Both BCR-ABL–dependent [16,17] and –independent [18] mechanisms of generating reactive oxygen species can contribute to overall genomic instability by inducing oxidative DNA damage such as double-strand breaks [19]. Furthermore, in vitro experiments have demonstrated that expression of BCR-ABL protein sensitizes cells to ionizing radiation [20] and causes cells to accumulate drug-induced DNA damage [21].…”

Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia

“…Point mutations, double strand breaks and translocations arising from oxidative stress are commonplace with elevated reactive oxygen species (ROS) generated by mitochondrial respiration mediating such DNA damage [1, 2]. Genetic lesions are of particular significance in stem cells.…”

“…The ‘reactive oxygen driven' solid tumor has previously been described, characterized by high levels of superoxide generation in tumor cells [13] that are often refractory to conventional chemotherapy, targeted therapy and radiation [2, 14]. Previously we have demonstrated the efficacy of the synthetic NADPH oxidase inhibitor imipramine blue (IB) to block the invasion of glioblastoma multiforme (GBM) into the brain parenchyma [15], and therefore, prolong survival in animal models likely through eradication of ROS-driven GBM stem cells.…”