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

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

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 2

Nipa–/– HSCs show reduced repopulating ability, limited self-renewal potential, and bias toward myeloid differentiation.

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Nipa–/– HSCs show reduced repopulating ability, limited self-renewal po...
(A) In vitro CFU assay of Nipa+/+ and Nipa–/– BMCs replated 4 times. Quantification of colonies and representative images. Data are from 4 independent experiments. n = 8 Nipa+/+; n = 8 Nipa–/–. (B) Representative flow cytometry profiles of BM chimerism of transplanted BMC mixture (day of Tx) injected into recipient mice in a competitive BM Tx assay. Quantified percentage of donor-derived BMCs normalized to WT, set 25%. n = 3. (C) Percentages of donor-derived PB cells analyzed by flow cytometry at the indicated time points in competitive BM Tx assay. Data from 3 independent Tx assays with at least 5 mice per group and genotype. (D) Representative flow cytometry profiles of CD45.1/CD45.2 BM chimerism after 6 months in recipient mice in competitive BM Tx assay. Quantified percentage of donor-derived BMCs. n = 8 Nipa+/+; n = 6 Nipa–/–. (E) Percentages of donor-derived PB cells analyzed by flow cytometry at the indicated time points in 3 serial LSK Tx assays. Data are from 2 independent Tx assays with 3–7 mice per group and genotype. (F) Percentages of LT-HSCs, ST-HSCs, and MPPs in 6- to 8-month-old Nipa+/+ and Nipa–/– BMCs after 5-FU injection on day –4, normalized to WT, set 100%. n = 9 Nipa+/+; n = 9 Nipa–/–. (G) Kaplan-Meier survival curve of 11-month-old Nipa+/x and Nipa–/– mice following regular 5-FU administration. n = 6 Nipa+/x; n = 7 Nipa–/–. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. An unpaired 2-tailed Student’s t test (A–F) or log-rank (Mantel-Cox) test (G) was used for statistical analyses. Data are presented as mean ± SD. See also Supplemental Figures 2–4.