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Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia

Lookup NU author(s): Professor Olaf Heidenreich

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Abstract

© 2018, The Author(s). BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.

Publication metadata

Author(s): Scherr M, Kirchhoff H, Battmer K, Wohlan K, Lee C-W, Ricke-Hoch M, Erschow S, Law E, Kloos A, Heuser M, Ganser A, Hilfiker-Kleiner D, Heidenreich O, Eder M

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2019

Volume: 33

Pages: 1313-1323

Online publication date: 13/12/2018

Acceptance date: 07/11/2018

Date deposited: 01/02/2019

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41375-018-0315-6

DOI: 10.1038/s41375-018-0315-6

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