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

Leukemia. 2019 Jun;33(6):1313-1323. doi: 10.1038/s41375-018-0315-6. Epub 2018 Dec 13.

Abstract

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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects*
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Dasatinib / administration & dosage
  • Dexamethasone / administration & dosage
  • Drug Resistance, Neoplasm
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Sulfonamides / administration & dosage
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Sulfonamides
  • Dexamethasone
  • venetoclax
  • Dasatinib