Influence of oxidation resistance 1 on disease progression in chronic myeloid leukemia
Weiqi Huang, Bin Liu, Liping Hu, Chi-Hao Luan, Priyam Patel, Elizabeth Bartom, Elizabeth A. Eklund
Weiqi Huang, Bin Liu, Liping Hu, Chi-Hao Luan, Priyam Patel, Elizabeth Bartom, Elizabeth A. Eklund
View: Text | PDF
Research Article Hematology Oncology

Influence of oxidation resistance 1 on disease progression in chronic myeloid leukemia

Abstract

Survival in chronic myeloid leukemia (CML) was dramatically improved by development of tyrosine kinase inhibitors (TKIs) directed to the BCR:ABL1 oncogene. Unfortunately, ~30% of patients with CML develop TKI resistance during prolonged treatment, with enhanced blast crisis risk. Oxidation Resistance 1 (Oxr1) regulates antioxidant pathways that detoxify reactive oxygen species (ROS) generated by the phagocyte-NADPH oxidase. In the current studies, we found that Oxr1 expression increased in hematopoietic stem and progenitor cells (HSPCs) from CML mice versus controls, decreased during TKI-induced remission, and rose during chronic phase relapse. Oxr1 has long and short isoforms, and we found increased short, but decreased long, Oxr1 in mice or humans during CML relapse. We determined that long Oxr1 prevents ROS accumulation in CML marrow, but short Oxr1 is a dominant negative. Previously, we found exaggerated and sustained emergency granulopoiesis in CML mice, with repeated episodes facilitating relapse during TKI remission. In the current studies, we found knocking down Oxr1 in murine marrow further accelerated CML progression during this physiologic stress. We found increased DNA-damage in HSPCs from these mice, including a BCR:ABL1 kinase-domain mutation found in TKI-resistant human CML. These studies suggest that long Oxr1 detoxifies ROS to decrease mutagenesis in CML, but aberrant short Oxr1 expression enhances progression.

Authors

Weiqi Huang, Bin Liu, Liping Hu, Chi-Hao Luan, Priyam Patel, Elizabeth Bartom, Elizabeth A. Eklund

×

Figure 8

Mutagenesis in CML is increased by Oxr1 knockdown and emergency granulopoiesis.

Options: View larger image (or click on image) Download as PowerPoint
Mutagenesis in CML is increased by Oxr1 knockdown and emergency granulop...
Recipients of BCR:ABL1-transduced marrow were sacrificed in CP, and marrow transduced with Oxr1-specific shRNAs or scrambled control vectors was transplanted into secondary recipients. Secondary recipients were TKI-treated and injected every 4 weeks with Alum to induce emergency granulopoiesis episodes. Whole exome sequencing performed on GFP+ versus GFP– marrow mononuclear cells, or age-matched cells from non-CML mice were identified. (A) Increased mutations and clones in GFP+ cells during BC versus other conditions and in GFP– cells from CML mice during CP relapse versus cells from non-CML mice. Significant differences in mutations were found by 1-way ANOVA with Tukey correction. *P < 0.05, **P < 0.01, or ***P < 0.001. Data are shown as mean ± SD and n = 3. (B) Distinct mutation profiles are found during CP relapse with versus without Oxr1 knockdown or with CP relapse versus BC progression. Gene ontology identified differences in pathways regulated by identified mutations. For comparisons, an uncorrected P < 0.05 and FDR-adjusted P < 0.05 were considered significant, and differences are indicated by Log10. Three mice per cohort were analyzed. (C) Mutation profiles in CML mice with Oxr1 knockdown and BC during emergency granulopoiesis are consistent with ROS-induced DNA damage. Mutation profiles were subjected to COSMIC analysis to implicate mutagenesis mechanisms. Three mice per cohort were analyzed. (D) Venn diagram demonstrating BC-unique mutations. Few common mutations were identified in CP relapse with versus without Oxr1 knockdown.