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Now going back to Follicular lymphoma and the change in the DNA that was found in the tumor

tissue isolated from different patients with Follicular lymphoma. It turns out that in those B-cells that make up the tumor tissue, a translocation exists between two of the 23 different types of chromosomes found in the nucleus of every human cell. This translocation is between chromosomes 14, and 18. The lower arms of chromosome 14 and 18 are basically switched. The switch most likely happened during the development or differentiation of a particular B-cell, which then gave rise to the cancer. What happens to the genes that are located at the breakpoints on chromosome 14 and chromosome 18? What genes are located there in the first place? On chromosome 14, the translocation is in the locus that encodes an immunoglobulin heavy chain, also referred to as Ig heavy chain. Ig heavy chains are proteins that are part of a protein complex that B-cells exhibit on their cell surface. This protein complex is also often referred to as an antibody. Since exhibiting antibodies on their cell surface is one of the major jobs of a B-cell, many Ig heavy chains are needed. The Ig heavy chain gene is therefore very highly expressed in B-cells. This is accomplished through an enhancer which is located downstream of the Ig heavy chain transcription unit. On chromosome 18, the translocation is in a locus that was subsequently named Bcl-2, which stands for B-cell lymphoma gene 2. In the case of the t(14;18) translocation the critical modification to the DNA is the following. The Bcl-2 locus is split in its three prime untranslated region or UTR. The resulting Bcl-2 locus, lacking part of its three prime UTR and everything downstream is then fused to part of the Ig heavy chain locus, including part of its transcription unit, as well as its downstream cis-acting regulatory elements. These downstream cis-acting regulatory elements include the enhancer that causes high expression of the Ig heavy chain locus in B-cells.

This tail can mediate association with lipid bilayers. it showed no homology to any other known protein and its sequence did not suggest any specific function.18) translocation suggested that this protein plays an important role in the development of follicular lymphomas. The definition of an oncogene is a gene. Before I tell you about their results.18) translocation. when overexpressed or hyperactivated causes tumorigenesis. The Bcl-2 protein was therefore a novel protein of unknown function. The two important questions now to ask were what the Bcl-2 protein normally does and how it may it cause tumorigenesis. And the proto-oncogene is a gene which has a normal function.What's the consequence of this translocation for the bcl-2 gene? The consequence is that the bcl-2 gene now is under the control of this strong Bcell enhancer. Australia thought that one approach to answer these questions was to recapitulate in cells grown in culture what happens in cells harboring the t(14.18) translocation basically results in the inappropriate overexpression of the bcl-2 gene in B-cells. The t(14. I want to give you some background on oncogenes. the t(14. they therefore generated cell lines in which the bcl-2 gene could be overexpressed with the help of a viral promoter. which. However. highly expressed in B-cells. for example a mutation or . However. but which can turn into an oncogene when it becomes deregulated by. It was therefore a protein that was definitely worth to study. Vaux. and therefore. 3 investigators at the Walter & Eliza Hall Institute of Medical Research in Melbourne. They then analyze cells from these cell lines with and without bcl-2 overexpression. What kind of molecule or protein does the Bcl-2 locus code for? The human Bcl-2 locus codes for a protein of 239 amino acids that possesses a hydrophobic tail. in 1986 when the sequence of the Bcl-2 protein became available. Cory and Adams. Using mammalian cells grown in culture.

Compared to normal cells. However. Cory and Adams used are grown in the presence of growth factors. The cell lines that Vaux. if the growth factors are removed from the medium in which the cells are cultured. cells that over express make divide faster and proliferate in an uncontrolled manner. just like the bcl-2 gene. If the cells that Vaux. acceleration and promotion of cell proliferation. they divide happily and you only see a few cells at any given time point that undergo apoptosis. a number of oncogenes had already been identified and characterized. Cory and Adams found is a different mechanism. The c-myc gene is a proto-oncogene. They found that the overexpression of bcl-2 does not promote cell proliferation. which. the myc gene. Most of the cells will undergo the morphological changes that are typical for apoptosis such as shrinkage condensation and fragmentation. they found that it blocks apoptosis. But let me back up a bit. most if the cells will die by apoptosis. and in order to survive. can be affected by specific chromosomal translocations which lead to its overexpression in certain cells that then cause Burkitt's lymphoma. Cory and Adams found that the overexpression . Corey and Adams had generated for their experiments are cell lines that need what are called growth factors in the medium in order to proliferate. Instead. Now what happens if the bcl-2 gene is strongly expressed in these cells? Vaux. that was the mechanism known for oncogenes described at the time. for example.. Growth factors are small proteins that are made and secreted by cells and that are used to mediate communication between cells within a specific tissue. In the late 1980s. What about bcl-2? What Vaux. Myc overexpression causes tumorigenesis because the myc protein promotes cell proliferation. In the late 1980s when the bcl-2 gene was identified and characterized.rearrangement of its DNA sequence. This represented a new mechanism of action for oncogenes.

how it can it cause tumorigenesis. would divide faster in the presence of growth factors. The Bcl-2 protein can block apoptosis. For this reason these results suggested that the normal function of the bcl-2 gene is to block apoptosis. Bcl-2. for example. They divided and proliferated just like control cells. to instead survive. The overexpression of bcl-2 therefore causes a block in apoptosis. And one last note. The fact that this overexpression causes B-cells. had no big effect when the cells were grown in the presence of growth factors. But this was not the case for bcl-2. It is now well established that most tumors are not caused by one change to the DNA. The overexpression of bcl-2 in B-cells of patients with the t(14. that should die.18) translocation was probably the first of these changes to occur. proliferate faster. tumorigenesis could be initiated. If for example. they did not divide and proliferate. most cells survived and did not undergo apoptosis. Effects seen by overexpressing a particular gene. It therefore has anti-apoptotic activity. however. Vaux. What they observed instead is that. often reflect the gain of function phenotype of that gene. Based on their seminal findings which were published in 1988. and therefore. but by several changes to the DNA. The cells survived. [Music] . Cells that overexpress the myc oncogene. which most likely occur sequentially. Cory and Adams had identified the first protein with a role in apoptosis.of the bcl-2 gene in these cells. a secondary mutation occurs in a gene that normally functions to restrict cell proliferation and if this mutation inactivates this gene. and this turned out to be the case. if bcl-2 overexpression blocks apoptosis but has no effect on cell proliferation. after they removed the growth factors from the medium. allows second secondary mutations to occur in these cells.