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

J Clin Invest. 2020 Jun 1;130(6):2827-2844. doi: 10.1172/JCI126215.


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: Bone marrow; DNA repair; Hematology; Hematopoietic stem cells; Stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • NIPA protein, mouse
  • Nuclear Proteins