title: Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Reynolds
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Roderick
authors.affiliation: 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.
authors.forename: J L
authors.initials: JL
authors.lastname: LaBelle
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bird
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bodaar
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Colon
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: U
authors.initials: U
authors.lastname: Pyati
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.affiliation: 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.
authors.forename: L B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: 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.
authors.forename: S E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: 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.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
authors.affiliation: 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.
authors.forename: L D
authors.initials: LD
authors.lastname: Walensky
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: 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.
authors.forename: A
authors.identifier: 0000000202499007
authors.initials: A
authors.lastname: Gutierrez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D035683:MicroRNAs / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011804:Quinolines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007093:Imidazoles; C549214:MIRN19A microRNA, human; C489427:MYC protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C531198:dactolisib