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 Aj Oostendorp; Justus Duyster; Anna Lena Illert

doi:10.1172/JCI126215

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 LemeerBernhard 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 Aj Oostendorp, Justus Duyster, Anna Lena Illert

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2827-2844
Number of pages	18
Journal	Journal of Clinical Investigation
Volume	130
Issue number	6
DOIs	https://doi.org/10.1172/JCI126215
Publication status	Published - 1 Jun 2020

Keywords

Animals
Congenital Bone Marrow Failure Syndromes/genetics
Fanconi Anemia Complementation Group D2 Protein/genetics
Hematopoietic Stem Cells/metabolism
Mice
Mice, Knockout
Nuclear Proteins/deficiency
Protein Binding

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI126215

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Kreutmair, S., Erlacher, M., Andrieux, G., Istvanffy, R., Mueller-Rudorf, A., Zwick, M., Rückert, T., Pantic, M., Poggio, T., Shoumariyeh, K., Mueller, T. A., Kawaguchi, H., Follo, M., Klingeberg, C., Wlodarski, M., Baumann, I., Pfeifer, D., Kulinski, M., Rudelius, M., ... Illert, A. L. (2020). Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure. Journal of Clinical Investigation, 130(6), 2827-2844. https://doi.org/10.1172/JCI126215

@article{f0ba4c3814ad40dda31b2e02453cda0b,

title = "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.",

keywords = "Animals, Congenital Bone Marrow Failure Syndromes/genetics, Fanconi Anemia Complementation Group D2 Protein/genetics, Hematopoietic Stem Cells/metabolism, Mice, Mice, Knockout, Nuclear Proteins/deficiency, Protein Binding",

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

year = "2020",

month = jun,

day = "1",

doi = "10.1172/JCI126215",

language = "English",

volume = "130",

pages = "2827--2844",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "6",

}

Kreutmair, S, Erlacher, M, Andrieux, G, Istvanffy, R, Mueller-Rudorf, A, Zwick, M, Rückert, T, Pantic, M, Poggio, T, Shoumariyeh, K, Mueller, TA, Kawaguchi, H, Follo, M, Klingeberg, C, Wlodarski, M, Baumann, I, Pfeifer, D, Kulinski, M, Rudelius, M, Lemeer, S, Kuster, B, Dierks, C, Peschel, C, Cabezas-Wallscheid, N, Duque-Afonso, J, Zeiser, R, Cleary, ML, Schindler, D, Schmitt-Graeff, A, Boerries, M, Niemeyer, CM, Oostendorp, RA, Duyster, J & Illert, AL 2020, 'Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure', Journal of Clinical Investigation, vol. 130, no. 6, pp. 2827-2844. https://doi.org/10.1172/JCI126215

TY - JOUR

T1 - Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure

AU - Kreutmair, Stefanie

AU - Erlacher, Miriam

AU - Andrieux, Geoffroy

AU - Istvanffy, Rouzanna

AU - Mueller-Rudorf, Alina

AU - Zwick, Melissa

AU - Rückert, Tamina

AU - Pantic, Milena

AU - Poggio, Teresa

AU - Shoumariyeh, Khalid

AU - Mueller, Tony A

AU - Kawaguchi, Hiroyuki

AU - Follo, Marie

AU - Klingeberg, Cathrin

AU - Wlodarski, Marcin

AU - Baumann, Irith

AU - Pfeifer, Dietmar

AU - Kulinski, Michal

AU - Rudelius, Martina

AU - Lemeer, Simone

AU - Kuster, Bernhard

AU - Dierks, Christine

AU - Peschel, Christian

AU - Cabezas-Wallscheid, Nina

AU - Duque-Afonso, Jesus

AU - Zeiser, Robert

AU - Cleary, Michael L

AU - Schindler, Detlev

AU - Schmitt-Graeff, Annette

AU - Boerries, Melanie

AU - Niemeyer, Charlotte M

AU - Oostendorp, Robert Aj

AU - Duyster, Justus

AU - Illert, Anna Lena

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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.

AB - 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.

KW - Animals

KW - Congenital Bone Marrow Failure Syndromes/genetics

KW - Fanconi Anemia Complementation Group D2 Protein/genetics

KW - Hematopoietic Stem Cells/metabolism

KW - Mice

KW - Mice, Knockout

KW - Nuclear Proteins/deficiency

KW - Protein Binding

U2 - 10.1172/JCI126215

DO - 10.1172/JCI126215

M3 - Article

C2 - 32338640

SN - 0021-9738

VL - 130

SP - 2827

EP - 2844

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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