期刊
BLOOD ADVANCES
卷 1, 期 14, 页码 903-914出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2016003798
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资金
- Jose Carreras Leukemia Foundation
- Emmy Noether-Programme of the German Research Foundation (DFG) [KL-2374/2-1]
- DFG [LA 3680/2-1]
- Else Kroner-Fresenius-Stiftung [2015_A92]
- Hannover Medical School
- Hannover Biomedical Research School
- Max-Eder program from the German Cancer Aid [111743]
- DFG (Cluster of Excellence REBIRTH) [EXC 62/3, SFB738]
- National Institutes of Health, National Heart, Lung, and Blood Institute [U01 HL100001]
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 patientderived 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.
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