Our long-term goal is to understand the molecular mechanisms operative in proliferation and differentiation in human lymphocytes. T-cell leukemias provide an excellent resource for identification and characterization of genes that may alter proliferation/differentiation of lymphocytes. For example, molecular analysis of specific translocations in leukemic cells have led to identification of more than 15 proto-oncogenes. Furthermore, leukemic cells provide novel opportunities to identify mechanisms that may cause altered expression of proto-oncogenes, thus contributing to leukemogenesis. We have recently identified a putative proto-oncogene (Rhom-2) on chromosome Il at pl3. The Rhom-2 locus is the most frequent target of translocation involving T-cell receptor genes in T-cell acute lymphoblastic leukemias (ALL) in children suggesting that the Rhom-2 gene plays an important role in leukemogenesis. We will generate transgenic mice containing the Rhom-2 gene under an inducible promoter to directly demonstrate its role in T-cell leukemia and other tumors. Rhom-2 is not expressed in normal thymocytes or mature lymphocytes but it is highly expressed in leukemic blasts from most cases of T-ALL with llpl3 translocations. It is believed that this aberrant Rhom-2 expression contributes to leukemogenesis. We, therefore, plan to identify and characterize nucleotide sequences that control normal and inappropriate transcription of the Rhom-2 gene. In particular, we will test the hypothesis that the llpl3 translocation in most cases removes a negative transcriptional regulatory element of the Rhom-2 gene, resulting in its inappropriate expression. If our hypothesis is experimentally verified, we would have discovered a novel mechanism of proto-oncogene activation. After achieving remission, approximately one-third of the patients with T- ALL relapse due to resurgence of residual leukemic cells that cannot be detected during remission by morphologic methods. We have used a very sensitive polymerase chain reaction (PCR) based assay to detect minimum residual disease in T-ALL patients. Using a limited number of patients, we found that the PCR based assay has great potential in predicting impending relapse and in determining the efficacy of anti-leukemic therapy. We now plan to conduct a prospective study employing an adequate number of patients to assess the use of this technique in predicting relapse, monitoring the efficacy of anti-leukemic therapy, and long-term survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA043237-06A1
Application #
2091146
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1988-02-01
Project End
1999-01-31
Budget Start
1994-02-15
Budget End
1995-01-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Chen, X; Pan, Q; Stow, P et al. (2001) Quantification of minimal residual disease in T-lineage acute lymphoblastic leukemia with the TAL-1 deletion using a standardized real-time PCR assay. Leukemia 15:166-70
Davenport, J; Neale, G A; Goorha, R (2000) Identification of genes potentially involved in LMO2-induced leukemogenesis. Leukemia 14:1986-96
Davenport, J W; Fernandes, E R; Harris, L D et al. (1999) The mouse mitotic checkpoint gene bub1b, a novel bub1 family member, is expressed in a cell cycle-dependent manner. Genomics 55:113-7
Mao, S; Neale, G A; Goorha, R M (1997) T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2. Oncogene 14:1531-9
Neale, G A; Rehg, J E; Goorha, R M (1995) Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice. Blood 86:3060-71
Neale, G A; Mao, S; Parham, D M et al. (1995) Expression of the proto-oncogene rhombotin-2 is identical to the acute phase response protein metallothionein, suggesting multiple functions. Cell Growth Differ 6:587-96
Neale, G A; Pui, C H; Mahmoud, H H et al. (1994) Molecular evidence for minimal residual bone marrow disease in children with 'isolated' extra-medullary relapse of T-cell acute lymphoblastic leukemia. Leukemia 8:768-75
Koehler, M; Fitzgerald, T J; Goorha, R M et al. (1992) MKW, a novel hematopoietic antigen. Leukemia 6:985-92
Fitzgerald, T J; Neale, G A; Raimondi, S C et al. (1992) Rhom-2 expression does not always correlate with abnormalities on chromosome 11 at band p13 in T-cell acute lymphoblastic leukemia. Blood 80:3189-97
Neale, G A; Fitzgerald, T J; Goorha, R M (1992) Expression of the V(D)J recombinase gene RAG-1 is tightly regulated and involves both transcriptional and post-transcriptional controls. Mol Immunol 29:1457-66

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