In adult acute non-lymphocytic leukemia (ANLL), 30-50% of cases contain an activated N-ras oncogene or an activated Ki-ras oncogene with point mutations at codons 12, 13 or 61. These point mutations, although only a step in leukemic progression, represent useful genetic markers for distinguishing the leukemic cells from the normal cells in patients with acute leukemia. This is par- ticularly important since no suitable morphological, histochemical or immunological ANLL-specific markers are available. The long-term objective of the proposed research is to exploit the presence of an activated ras to monitor minimal residual disease in children undergoing chemotherapy for ANLL. The proposed approach includes development of procedures that utilize the coupling of the polymerase chain reaction with a forced cloning into plasmid libraries in order to increase the limits of sensitivity of detection to at least one malignant cell in 104 normal cells. Other approaches include: transfection and direct genomic sequencing to determine the frequency of childhood ANLL with an activated ras the frequency in which the ras alteration is preexistent or is a late addition to the leukemic phenotype; analysis of the extent of minimal residual disease during and after chemotherapy in ANLL patients with an activated ras oncogene and to determine whether this technique is useful for early diagnosis of relapse.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047983-03
Application #
3813058
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moshier, J A; Skunca, M; Wu, W et al. (1996) Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1. Nucleic Acids Res 24:1149-57
Morris, J F; Rauscher 3rd, F J; Davis, B et al. (1995) The myeloid zinc finger gene, MZF-1, regulates the CD34 promoter in vitro. Blood 86:3640-7
Barr, F G; Chatten, J; D'Cruz, C M et al. (1995) Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553-7
Bennicelli, J L; Fredericks, W J; Wilson, R B et al. (1995) Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains. Oncogene 11:119-30
Biegel, J A; Nycum, L M; Valentine, V et al. (1995) Detection of the t(2;13)(q35;q14) and PAX3-FKHR fusion in alveolar rhabdomyosarcoma by fluorescence in situ hybridization. Genes Chromosomes Cancer 12:186-92
Fredericks, W J; Galili, N; Mukhopadhyay, S et al. (1995) The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. Mol Cell Biol 15:1522-35
Amin, K M; Litzky, L A; Smythe, W R et al. (1995) Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma. Am J Pathol 146:344-56
Werner, H; Shen-Orr, Z; Rauscher 3rd, F J et al. (1995) Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression. Mol Cell Biol 15:3516-22
Hol, F A; Hamel, B C; Geurds, M P et al. (1995) A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome. J Med Genet 32:52-6
Macina, R A; Barr, F G; Galili, N et al. (1995) Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma. Genomics 26:1-8

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