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Requirement for deoxycytidine kinase in T and B lymphocyte development.

Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway that recycles products of DNA degradation. dCK phosphorylates and therefore activates nucleoside analog prodrugs frequently used in cancer, autoimmunity, and viral infections. In contrast to its well established therapeutic relevance, the biological function of dCK remains enigmatic. Highest levels of dCK expression are found in thymus and bone marrow, indicating a possible role in lymphopoiesis. To test this hypothesis we generated and analyzed dCK knockout (KO) mice. dCK inactivation selectively and profoundly affected T and B cell development. A 90-fold decrease in thymic cellularity was observed in the dCK KO mice relative to wild-type littermates. Lymphocyte numbers in the dCK KO mice were 5- to 13-fold below normal values. The severe impact of dCK inactivation on lymphopoiesis was unexpected given that nucleoside salvage has been thought to play a limited, "fine-tuning" role in regulating deoxyribonucleotide triphosphate pools produced by the de novo pathway. The dCK KO phenotype challenges this view and indicates that, in contrast to the great majority of other somatic cells, normal lymphocyte development critically requires the deoxyribonucleoside salvage pathway.

Pubmed ID: 20080663

Authors

  • Toy G
  • Austin WR
  • Liao HI
  • Cheng D
  • Singh A
  • Campbell DO
  • Ishikawa TO
  • Lehmann LW
  • Satyamurthy N
  • Phelps ME
  • Herschman HR
  • Czernin J
  • Witte ON
  • Radu CG

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 23, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: 5U54 CA119347
  • Agency: NCI NIH HHS, Id: P50 CA86306
  • Agency: NCI NIH HHS, Id: R24 CA92865
  • Agency: NCI NIH HHS, Id: T32 CA09297
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Deoxycytidine Kinase
  • Exons
  • Gene Targeting
  • Lymphoid Tissue
  • Lymphopoiesis
  • Mice
  • Mice, Knockout
  • Models, Biological
  • T-Lymphocytes