MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.

Animals Bone Marrow DNA Damage Fanconi Anemia / genetics Hematopoietic Stem Cells Humans Mice Transforming Growth Factor beta
CXCR4 DNA damage Fanconi anemia MYC bone marrow failure genotoxic stress hematopoietic stem cells p53 physiological stress single-cell RNA sequencing

Journal

Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472

Informations de publication

Date de publication:
07 01 2021
Historique:
received: 21 02 2020
revised: 11 05 2020
accepted: 08 09 2020
pubmed: 1 10 2020
medline: 20 5 2021
entrez: 30 9 2020
Statut: ppublish

Résumé

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-β 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.

Identifiants

DOI: 10.1016/j.stem.2020.09.004 PMID: 32997960 PMC: PMC7796920
pubmed: 32997960
pii: S1934-5909(20)30450-1
doi: 10.1016/j.stem.2020.09.004
pmc: PMC7796920
mid: NIHMS1634089
pii:
doi:

Substances chimiques

Transforming Growth Factor beta 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

33-47.e8

Subventions

Organisme : NHLBI NIH HHS
ID : P01 HL048546
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL052725
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Alfredo 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.

Kaiyang Zhang (K)

Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.

Anniina 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.

Jessica Filiatrault (J)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Chunyu Yang (C)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Martha Velázquez (M)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Elissa Furutani (E)

Dana Farber and Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.

Devorah C Goldman (DC)

Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.

Benilde García de Teresa (B)

Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.

Gilda Garza-Mayén (G)

Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.

Kelsey McQueen (K)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Larissa A Sambel (LA)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Bertha Molina (B)

Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.

Leda Torres (L)

Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.

Marisol González (M)

Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.

Eduardo Vadillo (E)

Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.

Rosana Pelayo (R)

Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Puebla 74360, Mexico.

William H Fleming (WH)

Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.

Markus Grompe (M)

Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.

Akiko Shimamura (A)

Dana Farber and Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.

Sampsa Hautaniemi (S)

Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.

Joel Greenberger (J)

Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

Sara 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.

Kalindi Parmar (K)

Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Alan D 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.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Moelle osseuse › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles dus à un défaut de réparation de l'ADN › Anémie de Fanconi › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système hématopoïétique › Cellules de la moelle osseuse › Cellules souches hématopoïétiques › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › MYC Promotes Bone Marrow Stem Cell Dysfunction...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › MYC Promotes Bone Marrow Stem Cell Dysfunction...