Cyclic hematopoiesis (CH) is a rare hematological disease caused byoscillatory production of blood cells by the marrow. CH occurs sporadicay usually in children, and in families autosomal dominant disorder. At 21 day intervals, patients regularly have severe neutropenia, fever, oropharyngeal inflammation and, on occasion, severe life-threatening infections. An analogous autosomal recessive disease occurs in grey collie dogs whose blood cells oscillate with 14 day periodicity. The applicants have identified and began evaluating five families with autosomal dominant cyclic hematopoiesis (ADCH) in order to utilize reverse genetics to identify the genetic locus. Preliminary statistical analyses of the families indicates that it is highly likely that this can be accomplished through linkage analysis. Using similar methods the applicants will investigate the genetic mechanisms of the disease in the collies. In the collies, the applicants have recently learned that recombinant canine G-CSF fully corrects the hematologic abnormality and propose further studies including the use of other canine growth factors, to investigate hematopoietic regulation in this interesting disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018951-18
Application #
2137260
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1980-07-01
Project End
1998-08-31
Budget Start
1995-09-15
Budget End
1998-08-31
Support Year
18
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Aprikyan, Andrew A G; Kutyavin, Tatyana; Stein, Steven et al. (2003) Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp Hematol 31:372-81
Aprikyan, Andrew A G; Liles, W Conrad; Boxer, Laurence A et al. (2002) Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia. J Pediatr Hematol Oncol 24:784-6
Aprikyan, A A; Dale, D C (2001) Mutations in the neutrophil elastase gene in cyclic and congenital neutropenia. Curr Opin Immunol 13:535-8
Aprikyan, A A; Liles, W C; Rodger, E et al. (2001) Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood 97:147-53
Dale, D C; Liles, W C; Garwicz, D et al. (2001) Clinical implications of mutations of neutrophil elastase in congenital and cyclic neutropenia. J Pediatr Hematol Oncol 23:208-10
Dale, D C; Person, R E; Bolyard, A A et al. (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96:2317-22
Aprikyan, A A; Liles, W C; Park, J R et al. (2000) Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 95:320-7
Horwitz, M; Benson, K F; Person, R E et al. (1999) Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 23:433-6
Dale, D C (1998) The discovery, development and clinical applications of granulocyte colony-stimulating factor. Trans Am Clin Climatol Assoc 109:27-36;discussion 36-8
Palmer, S E; Stephens, K; Dale, D C (1996) Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 66:413-22

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