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Leukemia. 2016 Mar;30(3):674-82. doi: 10.1038/leu.2015.294. Epub 2015 Oct 26.

Reprogramming human B cells into induced pluripotent stem cells and its enhancement by C/EBPα.

Author information

Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain.
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG) and University Pompeu Fabra (UPF), Barcelona, Spain.
Department of Hematology, University Hospital of Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain.
Servei d'Oncologia Radioteràpica, Hospital Clinic, Barcelona, Spain.
Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Asturias, Spain.
Hematology Department, Hospital Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Spain.
Differentiation and Cytometry Unit, Hematopoietic Innovative Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
Faculty of Medicine, Laboratory of Gene Regulation, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Research Center for Stem Cell Engineering and National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.


B cells have been shown to be refractory to reprogramming and B-cell-derived induced pluripotent stem cells (iPSC) have only been generated from murine B cells engineered to carry doxycycline-inducible Oct4, Sox2, Klf4 and Myc (OSKM) cassette in every tissue and from EBV/SV40LT-immortalized lymphoblastoid cell lines. Here, we show for the first time that freshly isolated non-cultured human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20+ B cells can be reprogrammed to iPSCs carrying complete VDJH immunoglobulin (Ig) gene monoclonal rearrangements using non-integrative tetracistronic, but not monocistronic, OSKM-expressing Sendai Virus. Co-expression of C/EBPα with OSKM facilitates iPSC generation from both CB- and PB-derived B cells. We also demonstrate that myeloid cells are much easier to reprogram than B and T lymphocytes. Differentiation potential back into the cell type of their origin of B-cell-, T-cell-, myeloid- and fibroblast-iPSCs is not skewed, suggesting that their differentiation does not seem influenced by 'epigenetic memory'. Our data reflect the actual cell-autonomous reprogramming capacity of human primary B cells because biased reprogramming was avoided by using freshly isolated primary cells, not exposed to cytokine cocktails favoring proliferation, differentiation or survival. The ability to reprogram CB/PB-derived primary human B cells offers an unprecedented opportunity for studying developmental B lymphopoiesis and modeling B-cell malignancies.

[Indexed for MEDLINE]

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