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MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.
Rodríguez, Alfredo; Zhang, Kaiyang; Färkkilä, Anniina; Filiatrault, Jessica; Yang, Chunyu; Velázquez, Martha; Furutani, Elissa; Goldman, Devorah C; García de Teresa, Benilde; Garza-Mayén, Gilda; McQueen, Kelsey; Sambel, Larissa A; Molina, Bertha; Torres, Leda; González, Marisol; Vadillo, Eduardo; Pelayo, Rosana; Fleming, William H; Grompe, Markus; Shimamura, Akiko; Hautaniemi, Sampsa; Greenberger, Joel; Frías, Sara; Parmar, Kalindi; D'Andrea, Alan D.
Afiliación
  • Rodríguez A; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • Zhang K; Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
  • Färkkilä A; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
  • Filiatrault J; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Yang C; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Velázquez M; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Furutani E; Dana Farber and Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
  • Goldman DC; Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
  • García de Teresa B; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • Garza-Mayén G; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • McQueen K; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Sambel LA; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Molina B; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • Torres L; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • González M; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
  • Vadillo E; Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
  • Pelayo R; Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Puebla 74360, Mexico.
  • Fleming WH; Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
  • Grompe M; Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
  • Shimamura A; Dana Farber and Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
  • Hautaniemi S; Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
  • Greenberger J; Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • Frías S; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico; Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Parmar K; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • D'Andrea AD; Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.
Cell Stem Cell ; 28(1): 33-47.e8, 2021 01 07.
Article en En | MEDLINE | ID: mdl-32997960
ABSTRACT
Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-ß pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Anemia de Fanconi Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Anemia de Fanconi Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article