Superoxide dismutase 2 (SOD2) contributes to genetic stability of native and T315I-mutated BCR-ABL expressing leukemic cells

Journal Article · Sun Apr 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.03.023· OSTI ID:23137214

Girerd, Sandrine ^[1]; Tosca, Lucie ^[2]; Herault, Olivier; Vignon, Christine ^[3]; Biard, Denis ^[4]; others, and

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1. CHU de Poitiers, Service d’Oncologie Hématologique et Thérapie Cellulaire, Poitiers (France)
2. INSERM U935, Poitiers, Université de Poitiers (France)
3. CHRU de Tours, Département d’Hématologie Biologique, Tours (France)
4. INSERM U935, Human Embryonic Stem Cell Core Facility, Université Paris Sud 11, Villejuif (France)

Highlights: • This is the first report evaluating the role of SOD2 in native and T351-mutated BCR-ABL-expressing cells and in a large cohort of CML patients. • shRNA-mediated SOD2 invalidation led to alteration in several chromosomal loci including in regions coding for glypican and β-defensin genes. • In leukemic cells silenced for SOD2 expression a specific down-regulation of the expression of PRDX2 gene was found. • Gene set enrichment analysis performed between two SOD2-dependent classes of CML patients revealed a significant enrichment of ROS pathway. • In a large cohort of patients with CML, a significant decrease of SOD2 mRNA was observed. • This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. Manganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted). In a large cohort of patients with chronic myeloid leukemia (CML), a significant decrease of SOD2 mRNA was observed. This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. The analysis of anti-oxidant gene expression analysis revealed a specific down-regulation of the expression of PRDX2 in UT7-BCR-ABL and UT7-T315I cells silenced for SOD2 expression. Gene set enrichment analysis performed between the two SOD2-dependent classes of CML patients revealed a significant enrichment of Reactive Oxygen Species (ROS) Pathway. Our data provide the first evidence for a link between SOD2 expression and genetic instability in CML. Consequently, SOD2 mRNA levels should be analyzed in prospective studies as patients with low SOD2 expression could be more prone to develop a mutator phenotype under TKI therapies.

• OSTI ID: 23137214
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 498; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
MANGANESE
MESSENGER-RNA
MYELOID LEUKEMIA
OXYGEN
SUPEROXIDE DISMUTASE
THERAPY