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• W4312921275 abstract "A rare subtype of acute myeloid leukemia (AML) is acute megakaryoblastic leukemia (AMKL). Recurrent and mutually exclusive oncogenic fusions are detected in AMKL and are considered the transforming event in this disease. AMKL usually affects children below 3 years of age and is associated with less than 40% cure rates. In addition, the development of genotype tailored therapies is urgently needed in AMKL but greatly limited by the paucity of primary sample material. Our research group has established synthetic human models of high-fatality pediatric AMKL, driven by distinct oncogenic fusions, which phenocopy the disease in a patho-physiological context in mice. Inducers of mitochondria-mediated apoptosis, so called BH3 mimetics, recently entered the therapeutic arena in pediatric leukemia with promising results. Therefore, we set out to investigate the potential of Venetoclax (inhibitor of BCL-2) and Navitoclax (inhibitor of BCL-2, BCL-XL and BCL-W) as novel therapeutic options as a bridge to curative bone marrow transplantation in this high-fatality infant leukemia. Our research demonstrates that genetic and pharmacological inhibition of the pro-survival BCL-2 family member BCL-XL results in significant induction of apoptosis in our models of AMKL. In contrast, inhibition of BCL-2 does not induce apoptosis in our models, which is currently the most investigated BCL-family member in the clinic for other subtypes of AML (Venetoclax). In addition, Navitoclax showed promising in vivo activity with a significant decrease in infiltrating leukemic cells in bone-marrow and spleen after drug treatment in comparison to vehicle-only controls. In summary, this project will bring mechanistic insight into the role of apoptotic pathways in AMKL and greatly accelerate the identification of novel therapeutic options in high-fatality infant AML. A rare subtype of acute myeloid leukemia (AML) is acute megakaryoblastic leukemia (AMKL). Recurrent and mutually exclusive oncogenic fusions are detected in AMKL and are considered the transforming event in this disease. AMKL usually affects children below 3 years of age and is associated with less than 40% cure rates. In addition, the development of genotype tailored therapies is urgently needed in AMKL but greatly limited by the paucity of primary sample material. Our research group has established synthetic human models of high-fatality pediatric AMKL, driven by distinct oncogenic fusions, which phenocopy the disease in a patho-physiological context in mice. Inducers of mitochondria-mediated apoptosis, so called BH3 mimetics, recently entered the therapeutic arena in pediatric leukemia with promising results. Therefore, we set out to investigate the potential of Venetoclax (inhibitor of BCL-2) and Navitoclax (inhibitor of BCL-2, BCL-XL and BCL-W) as novel therapeutic options as a bridge to curative bone marrow transplantation in this high-fatality infant leukemia. Our research demonstrates that genetic and pharmacological inhibition of the pro-survival BCL-2 family member BCL-XL results in significant induction of apoptosis in our models of AMKL. In contrast, inhibition of BCL-2 does not induce apoptosis in our models, which is currently the most investigated BCL-family member in the clinic for other subtypes of AML (Venetoclax). In addition, Navitoclax showed promising in vivo activity with a significant decrease in infiltrating leukemic cells in bone-marrow and spleen after drug treatment in comparison to vehicle-only controls. In summary, this project will bring mechanistic insight into the role of apoptotic pathways in AMKL and greatly accelerate the identification of novel therapeutic options in high-fatality infant AML." @default.
• W4312921275 created "2023-01-05" @default.
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• W4312921275 date "2022-01-01" @default.
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• W4312921275 title "3093 – SUBTYPE-SPECIFIC INDUCTION OF MITOCHONDRIAL APOPTOSIS AS A NOVEL THERAPEUTIC OPTION IN HIGH-FATALITY PEDIATRIC LEUKEMIA" @default.
• W4312921275 doi "https://doi.org/10.1016/j.exphem.2022.07.149" @default.
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