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SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis.

ABSTRACT: Mitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O₂^-) levels with increased accumulation of hydrogen peroxide (H₂O₂) in CLL cells vs. normal B-cells. Further analysis indicated that mitochondrial superoxide dismutase (SOD)2, which converts O₂^- into H₂O₂ remained deacetylated in CLL cells due to SIRT3 overexpression resulting its constitutive activation. In addition, catalase expression was also reduced in CLL cells suggesting impairment of H₂O₂-conversion into water and O₂ which may cause H₂O₂-accumulation. Importantly, we identified two CpG-islands in the catalase promoter and discovered that while the distal CpG-island (-3619 to -3765) remained methylated in both normal B-cells and CLL cells, variable degrees of methylation were discernible in the proximal CpG-island (-174 to -332) only in CLL cells. Finally, treatment of CLL cells with a demethylating agent increased catalase mRNA levels. Functionally, ROS accumulation in CLL cells activated the AXL survival axis while upregulated SIRT3, suggesting that CLL cells rapidly remove highly reactive O₂^- to avoid its cytotoxic effect but maintain increased H₂O₂-level to promote cell survival. Therefore, abrogation of aberrantly activated cell survival pathways using antioxidants can be an effective intervention in CLL therapy in combination with conventional agents.

SUBMITTER: Maiti GP

PROVIDER: S-EPMC8129117 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2011-03-08 | GSE27701 | GEO

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