title: Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency.
abstract: XRCC4-like factor (XLF/Cernunnos) is a component of the nonhomologous end-joining (NHEJ) pathway of double-strand DNA break repair. XLF-deficient patients develop a severe progressive lymphocytopenia. Although NHEJ is required for V(D)J recombination and lymphocyte development, XLF-deficient mice have normal V(D)J recombination, highlighting the need for an alternative mechanism for the lymphocytopenia. Here, we report that XLF-deficient mice recapitulate the age-dependent lymphocytopenia of patients. We show that XLF deficiency leads to premature aging of hematopoietic stem cells (HSCs), measured by decreased functional capacity in transplantation assays, preferential myeloid reconstitution, and reduced self-renewal at a young age. We propose that premature aging of HSCs, together with previously reported defects in class-switch recombination and memory immune response, underlies the progressive and severe lymphocytopenia in XLF-deficient patients in the absence of measurable V(D)J recombination defects.
authors: Morgan Stanley Children's Hospital of New York-Presbyterian, Department of Pediatrics, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Research Center.
authors: Serine
authors: S
authors: Avagyan
authors: Herbert Irving Comprehensive Cancer Research Center, Division of Oncology, Department of Medicine, and.
authors: Michael
authors: M
authors: Churchill
authors: Department of Pediatrics, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Research Center, Pathobiology Graduate Program, College for Physicians and Surgeons, Columbia University Medical Center, New York, NY; and.
authors: Kenta
authors: K
authors: Yamamoto
authors: Department of Pediatrics, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Research Center, Pathobiology Graduate Program, College for Physicians and Surgeons, Columbia University Medical Center, New York, NY; and.
authors: Jennifer L
authors: JL
authors: Crowe
authors: Department of Pediatrics, Institute for Cancer Genetics.
authors: Chen
authors: C
authors: Li
authors: Department of Pediatrics, Institute for Cancer Genetics.
authors: Brian J
authors: BJ
authors: Lee
authors: Department of Statistics, Columbia University, New York, NY.
authors: Tian
authors: T
authors: Zheng
authors: Division of Oncology, Department of Medicine, and.
authors: Siddhartha
authors: S
authors: Mukherjee
authors: Morgan Stanley Children's Hospital of New York-Presbyterian, Department of Pediatrics, Institute for Cancer Genetics.
authors: Shan
authors: S
authors: Zha
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008231:Lymphopenia / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D004268:DNA-Binding Proteins; C519508:XLF protein, mouse