Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.

Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.

Essential role of limiting telomeres in the pathogenesis of Werner syndrome.

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.

Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter.

BACKGROUND: Current theory on the etiology of Langerhans cell histiocytosis (LCH), formerly Histiocytosis-X, is that abnormality(ies) of the immune system are responsible for dysregulation of Langerhans cells (LC) in patients' lesions. Among the known abnormalities in LCH patients are increased amounts of tumor necrosis factor alpha (TNF-alpha) and other cytokines in the lesions. PROCEDURE: We investigated the human leukocyte antigen (HLA) phenotypes of 29 patients and 37 healthy family members to determine if any haplotypes segregate with the presence or locations of the disease. The lymphocyte subsets for 22 patients and 11 family members were also determined. RESULTS: Patients with single bone, multiple bone, or multi-system LCH had different relative proportions of HLA types. Patients presenting with single bone disease had an especially high frequency of the DR4 type. In this patient group, every Caucasian patient had either Cw7 or DR4. Lymphopenia was documented in patients who had been off therapy as well as those who only had surgical curetage of their lesions. Family members also had low numbers of T lymphocytes. There were fewer mutations of the TNF-alpha promoter in patients than in the general population. CONCLUSIONS: Although there is an increased percentage of LCH patients with DR4 and/or Cw7 there was also an increased prevalence of this antigen as well as lymphopenia among unaffected family members. Additional genetic and/or environmental factors are necessary to explain this association. TNF-alpha promoter mutations are not responsible for the increased production of this cytokine.