Abstract

Chronic myelogenous leukemia (CML) is a multipotent stem cell disorder associated in over 90% of cases with the Philadelphia chromosome (Ph?1?). Alterations of the c-abl oncogene have been previously described in CML: this gene is translocated to the Ph?1? in cases of CML; and an abnormally large c-abl RNA transcript (8.2 kb vs the normal 7.4 and 6.6 kb), which may be related to the pathogenesis of CML, has been observed in Ph?1? positive CML cells. This proposal aims to molecularly clone DNA sequences which are present in the 8.2 kb abl CML transcript but not in the normal 7.4 and 6.6 kb abl transcripts. This DNA clone will provide a relatively simple means of quantitating expression of the 8.2 kb abl transcript in various CML cells. The following questions will be specifically addressed using the 8.2 kb abl transcript-specific probe: (1) How strict is the correlation between the presence of the Ph?1? and the presence of the abnormal 8.2 kb abl transcript? (2) Are there subsets of CML cells in which the 8.2 kb abl transcript is preferentially expressed? (3) Is there a relationship between enhanced expression of this transcript and progression of CML from chronic to blast crisis phase? In addition, if there is found to be a strict correlation between the presence of the Ph?1? and the presence of the 8.2 kb abl transcript, then attempts will be made to perfect a diagnostic and prognostic test for CML utilizing the 8.2 kb abl transcript-specific DNA probe. This test potentially would be more rapid, simpler, and capable of screening a larger number of samples that the cytogenetic demonstration of the Ph?1? which currently is the best diagnostic marker for CML. (6)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040728-02
Application #
3181034
Study Section
(SSS)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109

  Publications

Radich, J P; Kopecky, K J; Willman, C L et al. (1990) N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76:801-7
Andrews 3rd, D F; Collins, S J; Reddy, A L (1990) Absence of the c-Ha-ras codon 61 point mutation in murine solid tumors induced by subcutaneously applied 7,12-dimethylbenzanthracene. Cancer Lett 54:139-45
Collins, S J; Howard, M; Andrews, D F et al. (1989) Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia. Blood 73:1028-32
Hickstein, D D; Back, A L; Collins, S J (1989) Regulation of expression of the CD11b and CD18 subunits of the neutrophil adherence receptor during human myeloid differentiation. J Biol Chem 264:21812-7
Collins, S J (1988) Direct sequencing of amplified genomic fragments documents N-ras point mutations in myeloid leukemia. Oncogene Res 3:117-23
Hickstein, D D; Howard, M; Meuller, L et al. (1988) Expression of the beta-subunit of the human leukocyte adherence receptor depends upon cell type and stage of differentiation. J Immunol 141:4313-7
Hickstein, D D; Hickey, M J; Collins, S J (1988) Transcriptional regulation of the leukocyte adherence protein beta subunit during human myeloid cell differentiation. J Biol Chem 263:13863-7
Andrews 3rd, D F; Collins, S J (1987) Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis. Leukemia 1:718-24
Collins, S J; Groudine, M T (1987) Chronic myelogenous leukemia: amplification of a rearranged c-abl oncogene in both chronic phase and blast crisis. Blood 69:893-8
Collins, S; Coleman, H; Groudine, M (1987) Expression of bcr and bcr-abl fusion transcripts in normal and leukemic cells. Mol Cell Biol 7:2870-6

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