Transforming and Tumorogenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosin-Kinase
| Autor: | Marta Galán-Díez, Álvaro Cuesta-Domínguez, Mara Ortega, María Ángeles Figuera, Matilde Santos-Roncero, Juan A. Bueren, Peter P. Sayeski, Paula Río, Jaqueline Sayyah, Juan Luis Steegmann, E. Arranz, Cristina Ormazábal, Elena Fernández-Ruiz, José L. Vizmanos |
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| Rok vydání: | 2009 |
| Předmět: |
Kinase
Immunology breakpoint cluster region food and beverages Myeloid leukemia Cell Biology Hematology Biology medicine.disease medicine.disease_cause Biochemistry Fusion protein Molecular biology Fusion gene hemic and lymphatic diseases Acute lymphocytic leukemia medicine Carcinogenesis hormones hormone substitutes and hormone antagonists Interleukin 3 |
| Zdroj: | Blood. 114:4683-4683 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v114.22.4683.4683 |
| Popis: | Abstract 4683 Chromosomal translocations in human tumors frequently produce fusion genes whose chimeric protein products play an essential role in oncogenesis. Recent reports have found a BCR-JAK2 fusion gene in cases of chronic or acute myeloid leukemia, but the protein had not been characterized. We describe a BCR-JAK2 fusion gene by fluorescence in situ hybridization and RT-PCR amplification from bone marrow at diagnosis of a patient with acute lymphoblastic leukemia. After induction therapy, real time PCR showed persistent molecular response correlating with hematological remission maintained up to present. BCR-JAK2 is a 110 KDa chimeric protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis showed that BCR-JAK2 was constitutively phosphorylated and was located to the cytoplasm. BCR-JAK2 transformed the IL-3-dependent murine hematopoietic cell line Ba/F3 into IL-3 independent growth and induced STAT5b phosphorylation and translocation into the cell nuclei. The treatment with a JAK2 inhibitor abrogated BCR-JAK2 and STAT5b phosphorylation, leading to apoptosis of transformed Ba/F3 cells. To test whether BCR-JAK2 has tumorogenic ability in vivo, we performed experiments with nude mice, in which we injected subcutaneously cells transduced with the control vector and cells expressing BCR-JAK2. Notably, we only obtained tumors in the flank injected with BCR-JAK2 expressing cells, thus confirming the tumorogenic activity of the BCR-JAK2 fusion protein. We conclude that BCR-JAK2 is a new tyrosine-kinase that induces proliferation and cell survival, which can be abrogated by JAK2 inhibitors. In vitro studies demonstrate that BCR-JAK2 displays transforming activity. Moreover, the nude mice model reveals its ability to cause tumors. Disclosures: No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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