Scattolin 2016 Abstract Mito Xmas Meeting Innsbruck

Mitochondrial reactive oxygen species prime T-cell acute lymphoblastic leukemia to cell death by engaging the OMA1-OPA1 axis.

Link:

Silic-Benussi M, Scattolin G, Cavallari I, Minuzzo S, Basso G, Indraccolo S, D’Agostino DM, Ciminale V (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

Approximately 20% of T-cell acute lymphoblastic leukemia (T-ALL) patients do not respond to current therapy, and their clinical outcome is dismal.

In the present study we show that leukemic cells isolated from T-ALL patients as well as cell lines stabilized in vitro or propagated in vivo as xenografts exhibit high levels of mitochondrial reactive oxygen species (ROS). Interestingly, raising mitochondrial ROS using NS1619, a small molecule that opens the mitochondrial BK K⁺ channel, induced death of leukemic cells from T-ALL patients and T-ALL cell lines but not of primary normal thymocytes or PBMC. These effects were enhanced by blunting ROS-scavenging pathways with dehydroepiandrosterone (DHEA), an inhibitor of the pentose phosphate pathway (PPP). The combination of NS1619 and DHEA led to proteolytic processing of OPA1, an inner mitochondrial membrane protein that controls cristae remodeling, cytochrome c release and apoptosis. OPA1 cleavage was dependent upon both ROS and the OMA1 mitochondrial protease. Furthermore, OPA1 cleavage induced by treatment with NS1619 and DHEA primed T-ALL cells to apoptosis induced by TNF-Related Apoptosis Inducing Ligand (TRAIL). These findings suggest that engaging the OMA1-OPA1 axis by raising mitochondrial ROS may prove to be an effective strategy for apoptotic priming of refractory T-ALL, which poses a major clinical challenge at present.

Labels: MiParea: mt-Structure;fission;fusion Pathology: Cancer Stress:Cell death, Oxidative stress;RONS Organism: Human Tissue;cell: Blood cells, Lymphocyte Preparation: Intact cells

Event: B2, Oral Labelled by author

Affiliations

Silic-Benussi M(1,2), Scattolin G(1), Cavallari I(1), Minuzzo S(1), Basso G(3), Indraccolo S(2), D’Agostino DM(4), Ciminale V(1,2)

Dept Surgery, Oncology, Gastroenterology, Univ Padova, Italy
Istituto Oncologico Veneto-IRRCS, Padova, Italy
Dept Woman Child Health, Haemato-Oncology Division, Univ Padova, Italy
Dept Biomedical Sc, Univ Padova, Italy