Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure.
J Clin Invest
; 130(6): 2827-2844, 2020 06 01.
Article
em En
| MEDLINE
| ID: mdl-32338640
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Proteínas Nucleares
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Proteína do Grupo de Complementação D2 da Anemia de Fanconi
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Síndrome Congênita de Insuficiência da Medula Óssea
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha