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. 2014 Sep 4;124(10):1622-5.
doi: 10.1182/blood-2014-05-574863. Epub 2014 Jul 29.

Hematopoietic Stem Cell Dysfunction Underlies the Progressive Lymphocytopenia in XLF/Cernunnos Deficiency

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Free PMC article

Hematopoietic Stem Cell Dysfunction Underlies the Progressive Lymphocytopenia in XLF/Cernunnos Deficiency

Serine Avagyan et al. Blood. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Progressive lymphocytopenia in XLF-deficient mice. (A) Representative flow cytometric analysis of B cells in the spleen of XLF−/− mice and XLF+/+ littermates. Absolute number of mature B220+IgM+ B cells (B) and CD4+CD8 T cells (C) in the spleen of XLF−/− mice and XLF+/+ littermates; P < 2 × 10−7. (D) Representative flow cytometric analysis of B cells in the BM in XLF−/− mice and XLF+/+ littermates. (E) Percentage of total B220+ B cells in the BM of XLF−/− mice and XLF+/+ littermates; P = 1.4 × 10−7. n ≥ 3 per age group per genotype. Data represent mean ± standard deviation in all graphs. The P values in this figure were calculated by comparing the slope of regression lines between XLF+/+ and XLF−/− mice with Student t test. IgM, immunoglobulin M.
Figure 2
Figure 2
Functional decline of XLF-deficient HSCs with aging. (A) Representative flow cytometric analysis of lineagenegSca-1+c-Kit+CD150+CD48 HSCs in the BM in XLF−/− and control mice. (B) Frequency of HSCs in the BM at various ages of XLF−/− (n ≥ 3 per age group) and control mice (n ≥ 2 per age group). (C) Ratio of donor to competitor contribution within total MNCs and mature lineages in PB of primary recipients of BM cells from XLF−/− and XLF+/+ mice 10 weeks after transplantation; n ≥ 6 per age group per genotype. XLF−/− and XLF+/+ BM cells within each age group were transplanted with BM cells from a common competitor mouse for easy comparison. Different age groups (3, 6, and 12 months old) were not transplanted at the same time; therefore, absolute chimerism between various age groups of the same genotype cannot be directly compared. (D) Myeloid donor/competitor ratio vs B-cell donor/competitor ratio in primary recipients of XLF−/− BM cells normalized to that of controls; n ≥ 6 per age group per genotype. (E) The δ log ratio within peripheral myeloid cells between secondary and primary transplantations for recipients of XLF+/+ or XLF−/− BM cells; n ≥ 4 per age group per genotype. (F) Ratio of donor to competitor contribution within PB MNCs, myeloid and B cells of primary recipients of purified HSCs from ≥23-month-old XLF+/− or XLF−/− mice with competitor BM cells 10 weeks after transplantation; n ≥ 6 per age group per genotype. (G) Donor-to-competitor ratio within BM lineagenegSca-1+c-Kit+CD150+ HSCs of primary recipients of 3-, 6-, and 12-month-old XLF+/+ (CTRL) and XLF−/− BM cells ≥20 weeks after transplantation, and primary recipients of ≥23-month-old XLF+/− (CTRL) and XLF−/− HSCs ≥17 weeks after transplantation; n ≥ 5 per age group per genotype. Data represent mean ± standard error of the mean. *P < .05, **P < .01. The P values in this figure were calculated using two-tailed Student t test assuming equal variance. FSC, forward scatter; N.S., not significant; SSC, side scatter.

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