Chronic myelogenous leukemia (CML) is a disorder in which the initial lesion is known to occur at the level of hemopoietic stem cells (HSCs). The leukemic cells of over 95 percent of CML patients harbor the Philadelphia (Ph), which occurred as the result of a reciprocal translocation between chromosomes 9 and 22. At the molecular level, this translocation generates the bcr/abl hybrid gene, whose product has elevated tyrosine kinase activity. These changes are very similar to those observed in a similarly altered and activated v-abl oncogene discovered in the mouse. The introduction of either the bcr/abl or v-abl oncogene into hemopoietic stem/progenitor cells and after their engraftment into recipient mice could produce a disease resembling CML in humans. Over the past few years, several investigators, including the principal investigator, have actively employed a mouse model to understand disease pathogenesis. To take it further, they are establishing a gene therapy mouse model for CML. By using fetal liver cells as a source of HSCs, they have shown that transplantable leukemia in mice can be developed after retroviral transfer of either bcr/abl or v-abl oncogene into these fetal HSCs. Furthermore, this mouse model has several aspects that resemble those in humans: (a) untransduced normal HSCs are also present in leukemic mice, and (b) expression of the activated abl oncogene in primitive stem cells is low in Ph +ve human multipotent stem/progenitor cells. In this application, the investigators wish to dissect the model further and to examine if retroviral gene transfer of the anti-bcr/abl sequences into leukemic HSCs would result in retardation or elimination of leukemia development in secondary recipients after retransplantation of single or few leukemic donor HSCs.
The specific aims are (1) to determine the proportion of bcr/abl transduced and untransduced long-term repopulating HSCs in leukemic mice; (2) to examine whether untransduced gp105 +ive HSCs have a competitive growth advantage over bcr/abl transduced gp105 +ive HSCs; (3) to verify the effectiveness of the antisense vector in vitro on the suppression of bcr/abl-mediated transformation or leukemia development; (4) to test the efficacy of the antisense therapy by gene transfer into leukemic HSCs using the in vivo mouse model of leukemogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA070854-01A1
Application #
2410862
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1997-08-01
Project End
2001-05-31
Budget Start
1997-08-01
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Temple University
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Chung, Siu-Wah; Arnott, John A; Yang, Yizeng et al. (2003) Presence of prepackaged mRNA in virions of DNA adenovirus. J Biol Chem 278:50635-40
Wong, Peter M C (2002) Hypothesis: Ran GTPase-based potential therapeutic interventions against lethal microbial infections. ScientificWorldJournal 2:684-9
Trump, David P; Mathias, Carla J; Yang, Zhenfan et al. (2002) Synthesis and evaluation of 99mTc(CO)(3)-DTPA-folate as a folate-receptor-targeted radiopharmaceutical. Nucl Med Biol 29:569-73
Wong, P M; Yuan, Q; Chen, H et al. (2001) A single point mutation at the 3'-untranslated region of Ran mRNA leads to profound changes in lipopolysaccharide endotoxin-mediated responses. J Biol Chem 276:33129-38
Daniel, R; Chung, S W; Eisenstein, T K et al. (2001) Specific association of Type I c-Abl with Ran GTPase in lipopolysaccharide-mediated differentiation. Oncogene 20:2618-25
Zhao, F; Yuan, Q; Sultzer, B M et al. (2001) The involvement of Ran GTPase in lipopolysaccharide endotoxin-induced responses. J Endotoxin Res 7:53-6
Yuan, Q; Zhao, F; Chung, S W et al. (2000) Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran. Proc Natl Acad Sci U S A 97:2852-7
Chen, H; Chung, S W; Wong, P M (2000) Expression of a truncated retroviral envelope gene enhances expression of normal cellular phenotypes. J Biomed Sci 7:514-22
Wong, P M; Chugn, S W; Sultzer, B M (2000) Genes, receptors, signals and responses to lipopolysaccharide endotoxin. Scand J Immunol 51:123-7
Wong, P M; Sultzer, B M; Chung, S W (2000) The potential of Lps(d)/Ran cDNA in gene therapy for septic shock. J Hematother Stem Cell Res 9:629-34

Showing the most recent 10 out of 11 publications