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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744114.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells
Authors:Pittermann, E.; Lachmann, N.; MacLean, G.; Emmrich, S.; Ackermann, M.; Gohring, G.; Schlegelberger, B.; Welte, K.; Schambach, A.; Heckl, D.; Orkin, S. H.; Cantz, T.; Klusmann, J. H.
Date of Publication (YYYY-MM-DD):2017-06-13
Title of Journal:Blood Adv
Volume:1
Issue / Number:14
Start Page:903
End Page:914
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Severe congenital neutropenia (SCN, Kostmann disease) is a heritable disorder characterized by a granulocytic maturation arrest. Biallelic mutations in HCLS1 associated protein X-1 (HAX1) are frequently detected in affected individuals, including those of the original pedigree described by Kostmann in 1956. To date, no faithful animal model has been established to study SCN mediated by HAX1 deficiency. Here we demonstrate defective neutrophilic differentiation and compensatory monocyte overproduction from patient-derived induced pluripotent stem cells (iPSCs) carrying the homozygous HAX1(W44X) nonsense mutation. Targeted correction of the HAX1 mutation using the CRISPR-Cas9 system and homologous recombination rescued neutrophil differentiation and reestablished an HAX1 and HCLS1-centered transcription network in immature myeloid progenitors, which is involved in the regulation of apoptosis, apoptotic mitochondrial changes, and myeloid differentiation. These findings made in isogenic iPSC-derived myeloid cells highlight the complex transcriptional changes underlying Kostmann disease. Thus, we show that patient-derived HAX1(W44X) -iPSCs recapitulate the Kostmann disease phenotype in vitro and confirm HAX1 mutations as the disease-causing monogenic lesion. Finally, our study paves the way for nonvirus-based gene therapy approaches in SCN.
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Cluster of Excellence REBIRTH, and. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA. Department of Human Genetics, Hannover Medical School, Hannover, Germany. Department of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital, University Hospital Tubingen, Tubingen, Germany. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; and. Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
Identifiers:ISSN:2473-9529 (Print) 2473-9529 (Linking) %R 10.1182/b... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/29296734 [ID No:2]
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