Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2

Article Abstract:

In lymphomas (tumors of lymphoid cells) composed of B lymphocytes, the supposed oncogene (a gene involved in the development of uncontrolled cell growth in cancer) bcl-2 is moved from one site of the chromosomes to another. The new site is next to the gene that encodes a portion of the immunoglobulin (antibody) molecules known as the heavy chain locus. Although the bcl-2 protein is not altered by the change in chromosomal location, its synthesis is no longer regulated, and bcl-2 is continually produced. This constant production of bcl-2 appears to enhance cell survival. Large amounts of bcl-2 has been shown to protect B and T lymphocytes, and also give them a growth advantage. Transgenic mice (mice that have been given a foreign gene during the embryonic stage) were given the bcl-2 gene that is attached to the portion of the immunoglobulin gene that allows constant production. These mice also have B lymphocytes that survive longer than expected when taken out of body and grown in tissue culture. However, these mice do not have an increased incidence of tumors. If transgenic mice are given the oncogene myc that is attached to the portion of the immunoglobulin gene that allows constant production, they have an increase incidence of tumors in B lymphocytes and in precursor cells that develop into B lymphocytes. In Burkitt's lymphoma, the oncogene myc is also moved from its normal chromosomal site to the chromosomal site that contains the heavy chain locus of the immunoglobulin molecule. It has been reported that the two oncogenes, bcl and myc, can act together to allow growth of B cells. In transgenic mice that have received both the bcl and myc oncogenes, B cells grow at a very fast rate and tumors develop faster than in mice with myc only. The tumors develop in a cell that appears to be a primitive precursor cell, perhaps a stem cell. Therefore, the two oncogenes act in cooperation to allow tumor induction of B lymphoid cells. (Consumer Summary produced by Reliance Medical Information, Inc.)

Physiological aspects, Genetically modified mice

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Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18)

Article Abstract:

Cells in follicular lymphoma (a malignancy of lymphoid tissue) typically show chromosomal alterations with a characteristic pattern. This pattern involves translocation, which in this case involves movement between chromosome 18 and chromosome 14, which is then designated t(14;18). This leads to translocation of a gene (Bcl-2), which then becomes aberrant, failing to help carry out programmed cell death in the normal manner. Under such circumstances, cells that would normally die survive longer. To learn more about the development of lymphomas in t(14;18) mice, malignant tissue from 18 cases in five mouse cell lines was evaluated. Diffuse large-cell immunoblastic lymphomas (DHL-1), a rapidly growing malignancy, were the type most often found, composed of B cells (another cell type of the immune system). Details are presented concerning the cellular characteristics of the other types of malignancies. The excess B cells had accumulated as a result of prolonged survival, rather than increased proliferation. The fact that all B cells in a particular tumor were from a single clone indicated that additional genetic changes had taken place after the initial cell expansion (which was polyclonal). Half of these lymphomas also had a c-myc gene (an oncogene) that had been rearranged. It is possible that Bcl-2 is a proto-oncogene, a gene that regulates (in this case, suppressing) cell death. The role of the t(14;18) in the development of malignant lymphoma is strengthened by these results, and this animal model seems to be an appropriate tool for understanding the development of this disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abnormalities, Development and progression, Chromosomes

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Small G proteins are expressed ubiquitously in lymphoid cells and do not correspond to Bcl-2

Article Abstract:

In a large percentage of B-cell lymphomas, tumors of the lymphatic system, a translocation (in which certain regions of chromosomes are moved to another chromosome) occurs between chromosome 14 and 18, which moves a portion of the oncogene (tumor-causing gene) Bcl-2. Because of the change in chromosomal region, the Bcl-2 gene is no longer regulated and the protein the gene encodes, Bcl-2, is produced in large amounts. The Bcl-2 protein has been shown to have a function in the survival of cells, in the enhancement of the growth of cells, and in uncontrolled growth, i.e. cancer. It was thought that Bcl-2 binds guanidine triphosphate nucleotide (GTP) and this binding is thought to mediate the biological effects of Bcl-2. The levels of GTP binding proteins (G proteins) were examined in lymphoid cells that expressed Bcl-2. Several small G proteins, which were the same size as Bcl-2, were found to be expressed, but the level of expression did not change in cancerous cells, as does Bcl-2. Using protein chemistry and cell biological techniques, the Bcl-2 protein was separated from the small G proteins. It was shown that Bcl-2 did not bind GTP directly. Thus, the biochemical role of Bcl-2 is not known and the mechanisms behind its role in uncontrolled growth remain unknown as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

GTP

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