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Lnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia
- Source :
- Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018)
- Publication Year :
- 2018
- Publisher :
- Nature Portfolio, 2018.
-
Abstract
- Fanconi anemia (FA) is a bone marrow failure (BMF) syndrome that arises from mutations in a network of FA genes essential for DNA interstrand crosslink (ICL) repair and replication stress tolerance. While allogeneic stem cell transplantation can replace defective HSCs, interventions to mitigate HSC defects in FA do not exist. Remarkably, we reveal here that Lnk (Sh2b3) deficiency restores HSC function in Fancd2−/− mice. Lnk deficiency does not impact ICL repair, but instead stabilizes stalled replication forks in a manner, in part, dependent upon alleviating blocks to cytokine−mediated JAK2 signaling. Lnk deficiency restores proliferation and survival of Fancd2−/− HSCs, while reducing replication stress and genomic instability. Furthermore, deletion of LNK in human FA-like HSCs promotes clonogenic growth. These findings highlight a new role for cytokine/JAK signaling in promoting replication fork stability, illuminate replication stress as a major underlying origin of BMF in FA, and have strong therapeutic implications.
- Subjects :
- 0301 basic medicine
Genome instability
DNA Replication
Male
congenital, hereditary, and neonatal diseases and abnormalities
DNA Repair
Science
General Physics and Astronomy
Mice, Inbred Strains
Biology
General Biochemistry, Genetics and Molecular Biology
Genomic Instability
03 medical and health sciences
Fanconi anemia
hemic and lymphatic diseases
FANCD2
medicine
Animals
Humans
lcsh:Science
Gene
Cells, Cultured
Adaptor Proteins, Signal Transducing
Bone Marrow Transplantation
Cell Proliferation
Mice, Knockout
Multidisciplinary
Fanconi Anemia Complementation Group D2 Protein
Bone marrow failure
Intracellular Signaling Peptides and Proteins
Hematopoietic stem cell
Membrane Proteins
nutritional and metabolic diseases
General Chemistry
medicine.disease
Hematopoietic Stem Cells
Cell biology
Transplantation
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Fanconi Anemia
Female
lcsh:Q
Stem cell
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....d946a94714b65e53df8c1cf479a0f7d1