LOSS OF THE F-BOX PROTEIN NIPA CAUSES BONE MARROW FAILURE
Author(s): ,
Stefanie Kreutmair
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
,
Miriam Erlacher
Affiliations:
Department of Pediatrics and Adolescent Medicine,University Medical Center Freiburg,Freiburg,Germany
,
Geoffroy Andrieux
Affiliations:
Institute of Molecular Medicine and Cell Research,Center of Biochemistry and Molecular Cell Research (ZBMZ),Freiburg,Germany
,
Rouzanna Istvanffy
Affiliations:
Department of Internal Medicine III,Klinikum rechts der Isar, Technical University of Munich,Munich,Germany
,
Hiroyuki Kawaguchi
Affiliations:
Department of Pediatrics,National Defense Medical College,Saitama,Japan
,
Marie Follo
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
,
Marcin Wlodarski
Affiliations:
Department of Pediatrics and Adolescent Medicine,University Medical Center Freiburg,Freiburg,Germany
,
Irith Baumann
Affiliations:
Institute of Pathology,Health Center Böblingen,Böblingen,Germany
,
Dietmar Pfeifer
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
,
Christine Dierks
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
,
Robert Zeiser
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
,
Detlev Schindler
Affiliations:
Department of Human Genetics,University of Würzburg,Würzburg,Germany
,
Annette Schmitt-Graeff
Affiliations:
Department of Pathology,University Medical Center Freiburg,Freiburg,Germany
,
Melanie Boerries
Affiliations:
Institute of Molecular Medicine and Cell Research,Center of Biochemistry and Molecular Cell Research (ZBMZ),Freiburg,Germany
,
Charlotte Niemeyer
Affiliations:
Department of Pediatrics and Adolescent Medicine,University Medical Center Freiburg,Freiburg,Germany
,
Robert Oostendorp
Affiliations:
Department of Internal Medicine III,Klinikum rechts der Isar, Technical University of Munich,Munich,Germany
,
Justus Duyster
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
Anna Lena Illert
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University Medical Center Freiburg,Freiburg,Germany
EHA Library. Kreutmair S. Jun 15, 2019; 267444; S861
Ms. Stefanie Kreutmair
Ms. Stefanie Kreutmair
Contributions
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Abstract

Abstract: S861

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 11:30 - 11:45

Location: Hall E106

Background

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function and cancer susceptibility. It is a major diagnostic challenge to distinguish between IBMFS (e.g. Fanconi anemia (FA)), myelodysplastic syndrome (MDS) type refractory cytopenia of childhood (RCC) and severe aplastic anemia, due to overlapping phenotypes and pathological mechanisms, as well as, limited diagnostic tests and cells available.

Aims

As therapeutic strategies differ in these entities, novel and clinical relevant biomarkers are urgently needed.

Methods

To examine the functional role of NIPA in the hematopoietic stem cell (HSC) compartment in vivo, we analyzed Nipa-/- and VavTg/wtNipacko/cko  mice. For human studies, we analyzed FA and RCC patients, which were enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) study. NIPA expression was determined by immunohistochemistry on trephine biopsy slides.

Results

In our knockout mouse model, Nipa deletion shows both a reduction of the HSC pool and a cell intrinsic long-term repopulation defect, with impaired self-renewal in serial transplantations. Furthermore, Nipa-/- HSCs are unable to resolve DNA damage and prone to cell death. Interestingly, induction of replication stress triggers the phenotypic reduction and functional decline of murine HSCs. After short-term Poly(I:C) treatment of young Nipa-/- mice we are able to show significantly reduced blood counts, diminished BM cellularity and lower LSK and LK levels. Even more remarkable are the results from the chronic stress assay: while control mice survive repeated Poly(I:C) injections for more than 400 days, all of the treated VavTg/wtNipacko/cko animals die due to complete BM failure, with a median latency of 354 days (p=0.001). At the time of death, WBC counts are strongly reduced (p<0.0001) and BM sections show substantial aplasia. Thus, loss of NIPA leads to a BM failure phenotype in mice resembling functional Fanc deficiency.

Based on pathological MMC sensitivity in vitro and the FA-like phenotype of Nipa-/- mice we postulated that Nipa deficiency might play a role in human disorders characterized by hypocellularity of the BM. We sequenced the NIPA gene in 5 patients with confirmed, but unclassified FA, who were negative for all so far described FA genes, but find no NIPA mutations in whole exome sequencing. We next focused on BM samples from children with MDS type RCC, a disease characterized by pancytopenia, BM dysplasia, normal blast percentage and often BM hypocellularity. As expected, FA patients with documented germline FANC gene mutation show physiological NIPA expression in their bone marrow. In contrast, only 13 out of 24 RCC patients show normal NIPA expression, while 11 patients display strongly reduced NIPA levels. Surprisingly, in all of the patients with defined germline mutation (i.e. in GATA2, SAMD9L or RUNX1) we find regular NIPA expression. Of the 18 patients without known genetic predisposition and with normal karyotype, 11 show a strong reduction in NIPA expression. Together with the findings in our mouse model this result indicates that a reduction of NIPA levels might contribute to hematopoietic failure in these patients.

Conclusion

Our study identifies NIPA as an IBMFS gene, which is significantly downregulated in a distinct subset of pediatric RCC patients, thereby emphasizing its impact as potential diagnostic marker and/or possible therapeutic target.

Session topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research

Keyword(s): Bone marrow failure, DNA damage, Fanconi anemia, Hematopoietic stem cell

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