Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

  • Leukemia. 2014 Sep;28(9):1819-27. doi: 10.1038/leu.2014.78.
C Reynolds  1 ,  J E Roderick  2 ,  J L LaBelle  3 ,  G Bird  4 ,  R Mathieu  1 ,  K Bodaar  1 ,  D Colon  4 ,  U Pyati  4 ,  K E Stevenson  5 ,  J Qi  6 ,  M Harris  7 ,  L B Silverman  8 ,  S E Sallan  8 ,  J E Bradner  6 ,  D S Neuberg  5 ,  A T Look  8 ,  L D Walensky  8 ,  M A Kelliher  2 ,  A Gutierrez  8
Affiliations
  • 1. Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
  • 3. 1] Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [3] Department of Pediatrics, University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
  • 4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 7. Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 8. 1] Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
PMID: 24552990 DOI: 10.1038/leu.2014.78
Abstract

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with Phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial Apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial Apoptosis, a phenotype that is dependent on the expression of proapoptotic Bim. In a conditional zebrafish model, MYC downregulation induced Bim expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active Akt. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced Bim upregulation and Apoptosis, indicating that Bim is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring Bim function in human T-ALL cells using a stapled peptide mimetic of the Bim BH3 domain had therapeutic activity, indicating that Bim repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial Apoptosis, T-ALL persisted despite MYC downregulation in 10% of Bim wild-type zebrafish, 18% of Bim heterozygotes and in 33% of Bim homozygous mutants (P=0.017). We conclude that downregulation of Bim represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

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