title: Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics.
abstract: It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland.
authors.forename: Nathiya
authors.initials: N
authors.lastname: Muthalagu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Bhola
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Weiting
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: McBrayer
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Cantlon
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Fisch
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Golomb-Mello
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Ryan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Neurosurgery, Kaiser Permanente, Sacramento, CA 95815, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Jian
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Corbett
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Marti
authors.initials: M
authors.lastname: Goldenberg
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Madsen
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Walsh
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sedivy
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, Scotland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Murphy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel Ruben
authors.initials: DR
authors.lastname: Carrasco
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Shenandoah
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Division of Hematology-Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Cardio-Oncology Program, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: anthony_letai@dfci.harvard.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D004317:Doxorubicin / Q000633:toxicity; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009928:Organ Specificity; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin
keywords: apoptosis; c-Myc; cardiotoxicity; cell death regulation; chemosensitivity; neurotoxicity; pediatric cancer; radiosensitivity; side effects of chemotherapy; side effects of radiation therapy