Reynolds, ChristineRoderick, Justine E.LaBelle, James L.Bird, GregoryMathieu, RonaldBodaar, KimberlyColon, DianaPyati, UjwalStevenson, Kristen E.Qi, JunHarris, MarianSilverman, LewisSallan, StephenBradner, James ENeuberg, DonnaLook, A.Walensky, LorenKelliher, Michelle A.Gutierrez, Alejandro2015-04-012014Reynolds, C., J. E. Roderick, J. L. LaBelle, G. Bird, R. Mathieu, K. Bodaar, D. Colon, et al. 2014. “Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.” Leukemia 28 (9): 1819-1827. doi:10.1038/leu.2014.78. http://dx.doi.org/10.1038/leu.2014.78.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351075Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant 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 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.en-UST-cell acute lymphoblastic leukemiaBIMAKTMYCapoptosisJournal Article2015-04-0110.1038/leu.2014.78