BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model
| Autor: | Ralph B. Arlinghaus, Feng Lin, Jiaxin Liu, Giuseppe Monaco, Hui Lin, Tong Sun, Clifton Stephens, John W. Belmont |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Cancer Research
Clone (cell biology) Fusion Proteins bcr-abl Mice SCID Biology medicine.disease_cause Philadelphia chromosome Mice Mice Inbred NOD hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Proto-Oncogene Proteins Gene expression Genetics medicine Serine Animals Humans RNA Messenger Kinase activity Phosphorylation Molecular Biology Oncogene Proteins breakpoint cluster region Oncogenes Protein-Tyrosine Kinases medicine.disease Gene Expression Regulation Proto-Oncogene Proteins c-bcr Cancer research Tyrosine Carcinogenesis K562 Cells K562 cells Chronic myelogenous leukemia |
| Zdroj: | Oncogene. 20(15) |
| ISSN: | 0950-9232 |
| Popis: | It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML). We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl. To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity. Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|