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Loss of the Fanconi anemia–associated protein NIPA causes bone marrow failure
Stefanie Kreutmair, … , Justus Duyster, Anna Lena Illert
Stefanie Kreutmair, … , Justus Duyster, Anna Lena Illert
Published April 27, 2020
Citation Information: J Clin Invest. 2020;130(6):2827-2844. https://doi.org/10.1172/JCI126215.
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Research Article Hematology Article has an altmetric score of 4

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

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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.

Authors

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

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Figure 5

Nipa-deficient cells display MMC hypersensitivity as a hallmark of FA.

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Nipa-deficient cells display MMC hypersensitivity as a hallmark of FA.
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(A) Western blot analysis of Nipa+/+ and Nipa–/– primary MEFs (untreated and treated +6 hours with 0.5 μM MMC) for FANCD2 and lamin. Quantification of relative non- and monoubiquitinated FANCD2 protein levels of Nipa+/+ and Nipa–/– primary MEFs is shown. n = 7 Nipa+/+; n = 7 Nipa–/–. (B) Quantification of γ-H2AX foci in untreated and 0.5 μM MMC–treated Nipa+/+ and Nipa–/– primary MEFs. No MMC: data from 2 independent experiments; n = 74 Nipa+/+, n = 112 Nipa–/–. +6 hours MMC: data from 4 independent experiments; n = 121 Nipa+/+, n = 93 Nipa–/–. (C) Immunofluorescence for γ-H2AX foci in untreated and 6-hour MMC-treated (0.5 μM) Nipa+/+ and Nipa–/– primary MEFs. Representative confocal microscopy images are shown. Original magnification, ×63. (D) Representative images of DAPI-stained metaphase spreads of untreated and MMC-treated (5 nM) Nipa+/+ and Nipa–/– spleen cells after 48 hours of in vitro growth. Arrow indicates chromosome radials. Original magnification, ×100. (E) Quantification of chromosome radials per cell of untreated and MMC-treated (5 and 10 nM) Nipa+/+ and Nipa–/– spleen cells after 48 hours of in vitro growth. No MMC: n =40 Nipa+/+; n = 40 Nipa–/–. +MMC: n = 20 Nipa+/+; n = 20 Nipa–/–. (F) Cell survival assay of Nipa+/+, Nipa–/–, and Fancd2–/– MEFs measured after 5 days of culture with the indicated concentrations of MMC. Data from 2 independent experiments are shown. n = 12 Nipa+/+; n = 12 Nipa–/–; n =12 Fancd2–/–. One-way ANOVA, P = 6.4 × 10–7 (5 nM); P = 4.9 × 10–6 (10 nM); P = 1.7 × 10–5 (20 nM); P = 1.0 × 10–4 (50 nM). Reported P values in the figure from unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. A paired (A) or unpaired (B and E) 2-tailed Student’s t test was used for statistical analyses. Data are represented as mean ± SD. See also Supplemental Figure 10.

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