title: Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.
abstract: Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.|Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Liu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.|Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Montserrat
authors.affiliation: Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Tarantino
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Nongluk
authors.initials: N
authors.lastname: Plongthongkum
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Masuda
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nivet
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsunekawa
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Rupa Devi
authors.initials: RD
authors.lastname: Soligalla
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: April
authors.initials: A
authors.lastname: Goebl
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Aizawa
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Na Young
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kim
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Ilir
authors.initials: I
authors.lastname: Dubova
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ruotong
authors.initials: R
authors.lastname: Ren
authors.affiliation: Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-1511, Luxembourg, Luxembourg.
authors.forename: Antonio
authors.initials: A
authors.lastname: Del Sol
authors.affiliation: Hematopoiesis and Gene Therapy Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid 28040, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid 28040, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid 28040, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Bueren
authors.affiliation: Department of Genetics and Microbiology and Center for Biomedical Network Research on Rare Diseases (CIBERER), Universitat Autonoma de Barcelona, Campus de Bellaterra s/n 08193 Bellaterra, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Trujillo
authors.affiliation: Department of Genetics and Microbiology and Center for Biomedical Network Research on Rare Diseases (CIBERER), Universitat Autonoma de Barcelona, Campus de Bellaterra s/n 08193 Bellaterra, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Surralles
authors.affiliation: G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16147 Genova Quarto, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappelli
authors.affiliation: G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16147 Genova Quarto, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dufour
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Concepcion Rodriguez
authors.initials: CR
authors.lastname: Esteban
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Juan Carlos Izpisua
authors.initials: JCI
authors.lastname: Belmonte
mesh_terms: D002454:Cell Differentiation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D044127:Epigenesis, Genetic; D005199:Fanconi Anemia / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D008954:Models, Biological; D013234:Stem Cells / Q000473:pathology*; D055815:Young Adult
chemical_list: C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein