Journal Article

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

Robert Zeiser, Melanie Boerries, Detlev Schindler, Simone Lemeer, Dietmar Pfeifer, Michal Kulinski, Marcin W. Wlodarski, Justus Duyster, Martina Rudelius, Geoffroy Andrieux, Marie Follo, Nina Cabezas-Wallscheid, Michael L. Cleary, Miriam Erlacher, Irith Baumann, Stefanie Kreutmair, Khalid Shoumariyeh, Melissa Zwick, Milena Pantic, Rouzanna Istvanffy, Hiroyuki Kawaguchi, Charlotte M. Niemeyer, Christine Dierks, Tony A. Mueller, Jesus Duque-Afonso, Cathrin Klingeberg, Tamina Rückert, Alina Mueller-Rudorf, Bernhard Kuster, Annette Schmitt-Graeff, Robert A.J. Oostendorp, Teresa Poggio, Christian Peschel, Anna Lena Illert

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Aging / Anemia / Animals / Apoptosis / Bias / Biomarkers / Biomedical research / Bone marrow / Breast cancer / Cancer / Congenital Bone Marrow Failure Syndromes / Congenital Bone Marrow Failure Syndromes - genetics / Congenital Bone Marrow Failure Syndromes - metabolism / Congenital Bone Marrow Failure Syndromes - pathology / Deoxyribonucleic acid / Disease susceptibility / DNA / DNA damage / DNA repair / Fanconi Anemia Complementation Group D2 Protein / Fanconi Anemia Complementation Group D2 Protein - genetics / Fanconi Anemia Complementation Group D2 Protein - metabolism / Fanconi syndrome / Fanconi's anemia / Genes / Genetic aspects / Hematopoietic Stem Cells / Hematopoietic Stem Cells - metabolism / Hematopoietic Stem Cells - pathology / Knockout / Mice / Mice, Knockout / Mutation / Myelodysplastic syndrome / Nuclear Proteins / Nuclear Proteins - deficiency / Nuclear Proteins - metabolism / Phenotypes / Protein Binding / Proteins / Stem cell transplantation / Stem cells