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Leukemia. 2014 Sep;28(9):1819-27. doi: 10.1038/leu.2014.78. Epub 2014 Feb 20.

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

Author information

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.

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.

PMID:
24552990
PMCID:
PMC4139485
DOI:
10.1038/leu.2014.78
[Indexed for MEDLINE]
Free PMC Article

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