The goal of the proposed research is to learn more about the pathogenesis, natural history and treatment of human hemopoietic neoplasms by using the naturally occurring cellular mosaicism found in females heterozygous for the enzyme glucose-6- phosphate dehydrogenase (G6PD) or for a DNA marker such as a variant in the nucleotide sequence of hypoxanthine phosphorbosyl transferase (HPRT). Normal and abnormal hemopoietic and other cells will be studied directly and previously described methods will be used to grow hemopoietic cells in long-term marrow cultures, lymphocyte suspension cultures and in semi-solid media (as colonies).
Specific aims of the proposed research include: 1) To investigate heterogeneity of acute nonlymphocytic leukemia (ANLL) in differentiative expression of the involved stem cells, in the pattern of remissions and in antigenic characteristics of leukemic progenitors. 2) To use monoclonal antibodies to enrich normal progenitors and eliminate leukemic progenitors by a combination of positive and negative selection for the normal and abnormal progenitors, respectively. 3) To substantiate the hypothesis that chronic myelogenous leukemia (CML) and many ANLLs have a multistep pathogenesis in which clonal proliferation of genetically unstable pluripotent stem cells antedates the development of characteristic cytogenetic abnormalities such as the Philadelphia chromosome (Ph). 4) To demonstrate the the Ph- negative cells that appear in CML patients treated with recombinant alpha interferon (IF alpha) are in fact normal nonclonal progenitors and that the in vivo response to IF alpha can be predicted from the response in long-term culture. 5) To document the suggestions that Simian virus 40 (SV40)-transformed marrow stromal (""""""""microenvironmental"""""""") cells in long-term marrow cultures can be grown as colonies in semi-solid media and that they share a common stem cell with hemopoietic progenitors. 6) To characterize the differentiation antigenic phenotype of the pre-colony-forming cell we recently identified in marrow long- term cultures and to demonstrate that it is pluripotent for the lymphoid as well as the myeloid lineages. It is hoped that the results of the proposed work will contribute to the understanding of human leukemogeneis and to attainment of the goal of preventing the malignancies or providing a basis for rational therapy. One potential application of the ability to distinguish normal from leukemic progenitor cells and to selectively eliminate the latter cells is the treatment in vitro of remission marrow cells from patients with ANLL prior to autologous transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA016448-20
Application #
2086483
Study Section
Special Emphasis Panel (NSS)
Project Start
1978-09-30
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
20
Fiscal Year
1994
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
Raskind, W H; Niakan, K K; Wolff, J et al. (2000) Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia. Blood 95:2262-8
Raskind, W H; Bolin, T; Wolff, J et al. (1998) Further localization of a gene for paroxysmal dystonic choreoathetosis to a 5-cM region on chromosome 2q34. Hum Genet 102:93-7
Chansky, H; Robbins, J R; Cha, S et al. (1998) Expression of cartilage extracellular matrix and potential regulatory genes in a new human chondrosarcoma cell line. J Orthop Res 16:521-30
Raskind, W H; Conrad 3rd, E U; Matsushita, M et al. (1998) Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat 11:231-9
Raskind, W H; Steinmann, L; Najfeld, V (1998) Clonal development of myeloproliferative disorders: clues to hematopoietic differentiation and multistep pathogenesis of cancer. Leukemia 12:108-16
Higano, C S; Chielens, D; Raskind, W et al. (1997) Use of alpha-2a-interferon to treat cytogenetic relapse of chronic myeloid leukemia after marrow transplantation. Blood 90:2549-54
Horwitz, M; Benson, K F; Li, F Q et al. (1997) Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2. Am J Hum Genet 61:873-81
Raskind, W H; Pericak-Vance, M A; Lennon, F et al. (1997) Familial spastic paraparesis: evaluation of locus heterogeneity, anticipation, and haplotype mapping of the SPG4 locus on the short arm of chromosome 2. Am J Med Genet 74:26-36
Raskind, W H; Conrad, E U; Matsushita, M (1996) Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas. Genes Chromosomes Cancer 16:138-43
Raskind, W H; Conrad, E U; Chansky, H et al. (1995) Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet 56:1132-9

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