BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia

Oncotarget. 2016 May 10;7(19):26926-34. doi: 10.18632/oncotarget.8731.

Abstract

Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

Keywords: BIM; apoptosis; oncogene inactivation; targeted therapies.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Bcl-2-Like Protein 11 / genetics*
  • Bcl-2-Like Protein 11 / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Doxycycline / pharmacology
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Mice, Transgenic
  • MicroRNAs / genetics
  • Oncogenes / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA Interference

Substances

  • Bcl-2-Like Protein 11
  • MIRN17-92 microRNA, mouse
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins p21(ras)
  • Doxycycline