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Acute Leukemias

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

Leukemia volume 28, pages 1819–1827 (2014)Cite this article

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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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Acknowledgements

This work was supported by the National Institutes of Health/National Cancer Institute Grant CA167124 and by a grant from the William Lawrence Blanche Hughes Foundation. AG is a Research Fellow of the Gabrielle’s Angel Foundation for Cancer Research. We thank Domenico Accili for the FOXO-D256Δ construct, and Lin He for the MSCV-19a-20-19b construct, both of which were obtained from Addgene. We also thank Dean Felsher for the murine T-ALL cell line 4188.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    C Reynolds, J L LaBelle, R Mathieu, K Bodaar, L B Silverman, S E Sallan, A T Look, L D Walensky & A Gutierrez

  2. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    J E Roderick & M A Kelliher

  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J L LaBelle, G Bird, D Colon, U Pyati, L B Silverman, S E Sallan, A T Look, L D Walensky & A Gutierrez

  4. Department of Pediatrics, University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    J L LaBelle

  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    K E Stevenson & D S Neuberg

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    J Qi & J E Bradner

  7. Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    M Harris

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Correspondence to A Gutierrez.

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Competing interests

LDW is a scientific advisory board member and consultant for Aileron Therapeutics. The Dana-Farber Cancer Institute has filed patents on and licensed drug-like derivatives of JQ1 to Tensha Therapeutics for clinical translation as cancer therapeutics. JEB and the Dana-Farber Cancer Institute have been granted equity (minority) in Tensha, and JEB serves on the Board of Directors. The remaining authors declare no conflict of interest.

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Reynolds, C., Roderick, J., LaBelle, J. et al. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia 28, 1819–1827 (2014). https://doi.org/10.1038/leu.2014.78

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