DNA polymerase activity as an index of lymphocyte stimulation: studies in Down's syndrome

Ss, Agarwal; Bs, Blumberg; Bj, Gerstley; Wt, London; Ai, Sutnick; La, Loeb

doi:10.1172/jci106215

Cited by 75 publications

(29 citation statements)

References 34 publications

(27 reference statements)

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“…There are multiple studies that provide evidence of DNA repair defects in DS cells. Lymphocytes from persons with DS show lower baseline DNA repair 31 and exhibit increased sensitivity to phytohemagglutinin stimulation, 32 N-methyl-NЈ-nitro-N-nitrosoguanidine 31 and ␥-irradiation, 33 indicating an increased sensitivity to DNA oxidation, methylation, and strand breaks. Although more than one DNA repair pathway might be impacted by the DS phenotype, BER deficiency is a compelling candidate because it repairs these types of DNA damage.…”

Section: Dna Repair In Dsmentioning

confidence: 99%

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Cabelof

Patel

Chen

et al. 2009

Blood

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Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-␤-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-␤-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is com-

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Section: Dna Repair In Dsmentioning

confidence: 99%

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Cabelof

Patel

Chen

et al. 2009

Blood

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“…The features may be explicable by the age of subjects and immunological factors (Seger 1977). No elevation of SCEs were observed between DS and normal subjects (Biederman and Bowen 1977). This study showed slightly lower SCEs incidence in DS than in MR without statistical significance.…”

Section: Discussionmentioning

confidence: 52%

“…Responses to PHA in DS lymphocytes are rather variable such as hypersensitive, hyposensitive or normosensitive (Hayakawa et al 1968 ;Agarwal et al 1970 ;Fowler and Hollingsworth 1973) . The features may be explicable by the age of subjects and immunological factors (Seger 1977).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence has been provided that somatic cell chromosomes of DS are more susceptible than the normal chromosomes to biological, chemical, and physical factors (Sasaki and Tonomura 1969 ;Higurashi et al 1973 ;Countryman et al 1977) . However, the evidence so far presented has not been consistent on susceptibility and the cell cycle-time of lymphocytes in DS (Hayakawa et al 1968;Sasaki and Obara 1969;Agarwal et al 1970;Fowler and Hollingsworth 1973). This emphasized me to deal with the sister chromatid exchange (SCEs) in peripheral blood lymphocytes of DS that is a result of defective DNA-repair.…”

mentioning

confidence: 95%

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Sister Chromatid Exchanges and the Cell Cycle in Peripheral Blood Lymphocytes of Down Syndrome

Yanagisawa

1978

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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“…It has also been suggested [1,11,18,30,55,56] that it might be the immunological defects present in these disorders which are responsible for making such patients more susceptible to Au Ag.…”

Section: Discussionmentioning

confidence: 99%

The Incidence and Significance of Australia Antigen in Cancer Patients

Al‐Sarraf¹,

Kithier²,

Sardesai³

et al. 1973

Oncology

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Australia antigen (Au Ag) has been found in a higher frequency in patients with acute hepatitis, leukemia or Hodgkin’s disease as compared to normal subjects, in this study, 759 sera from 453 patients with advanced cancer were tested for Au Ag by the double radical immunodiffusion of Ouchterlony and by counter-electrophoresis. In addition, 40 patients with different non-neoplastic disease, 45 with malignancy of reticuloendothelial (RE) tissues, and 15 with viral hepatitis were tested for the presence of Au Ag. The Au Ag was found in 5 (1.1%) of the cancer patients, and in 3 (60%) of 5 patients with serum hepatitis. No Au Ag was found in any other sera tested. None of the 12 patients with hepatoma were found to have Au AG, while α-1-fetoprotein was found in the sera in 8 of the cases.

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DNA polymerase activity as an index of lymphocyte stimulation: studies in Down's syndrome

Cited by 75 publications

References 34 publications

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Sister Chromatid Exchanges and the Cell Cycle in Peripheral Blood Lymphocytes of Down Syndrome

The Incidence and Significance of Australia Antigen in Cancer Patients

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