Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure.

Autor: Kreutmair S; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Erlacher M; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, and., Andrieux G; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Institute of Medical Bioinformatics and Systems Medicine, University Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany., Istvanffy R; Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Mueller-Rudorf A; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Zwick M; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Rückert T; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Pantic M; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Poggio T; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Shoumariyeh K; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Mueller TA; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Kawaguchi H; Department of Pediatrics, National Defense Medical College, Saitama, Japan., Follo M; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Klingeberg C; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Wlodarski M; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, and., Baumann I; Institute of Pathology, Health Center Böblingen, Böblingen, Germany., Pfeifer D; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Kulinski M; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar., Rudelius M; Institute of Pathology, Ludwig Maximilian University Munich, Munich, Germany., Lemeer S; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany., Kuster B; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany., Dierks C; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Peschel C; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Cabezas-Wallscheid N; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany., Duque-Afonso J; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Zeiser R; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Cleary ML; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA., Schindler D; Department of Human Genetics, Institute of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany., Schmitt-Graeff A; Department of Pathology, Medical Center - University of Freiburg, Freiburg, Germany., Boerries M; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Institute of Medical Bioinformatics and Systems Medicine, University Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany., Niemeyer CM; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, and., Oostendorp RA; Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Duyster J; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Illert AL; Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2020 Jun 01; Vol. 130 (6), pp. 2827-2844.
DOI: 10.1172/JCI126215
Abstrakt: Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome-type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the Fanconi anemia (FA) pathway, which binds FANCD2 and regulates its nuclear abundance, making it essential for a functional DNA repair/FA/BRCA pathway. In a knockout mouse model, Nipa deficiency led to major cell-intrinsic defects, including a premature aging phenotype, with accumulation of DNA damage in hematopoietic stem cells (HSCs). Induction of replication stress triggered a reduction in and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the knockout mice with 100% penetrance. Taken together, the results of our study add NIPA to the short list of FA-associated proteins, thereby highlighting its potential as a diagnostic marker and/or possible target in diseases characterized by hematopoietic failure.
Databáze: MEDLINE