Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.


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.

DOI: 10.1038/ncomms5330

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@article{Liu2014ModellingFA, title={Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.}, author={Guang-Hui Liu and Keiichiro Suzuki and Mo Li and Jing Qu and Nuria Montserrat and Carolina Tarantino and Ying Gu and Fei Yi and Xiuling Xu and Weiqi Zhang and Sergio Ruiz and Nongluk Plongthongkum and Kun Zhang and Shigeo Masuda and Emmanuel Nivet and Yuji Tsunekawa and Rupa Devi Soligalla and April Goebl and Emi Aizawa and Na Young Kim and Jessica Kim and Ilir Dubova and Ying Li and Ruotong Ren and Chris Benner and Antonio Del Sol and Juan Bueren and Juan Pablo Trujillo and Jordi Surralles and Enrico Cappelli and Carlo Dufour and Concepcion Rodriguez Esteban and Juan Carlos Izpisua Belmonte}, journal={Nature communications}, year={2014}, volume={5}, pages={4330} }