Follicular Lymphoma of the Duodenum; Volume Rendered PET-CT , BCL 2 and Apoptosis

Figure 1: PET CT with VR fusion images. Intense abnormal 18-FDG uptake is seen in the second portion og the duodenum.

Figure 2: Diagram outlining the action of Bcl-2 on the apoptosis sequence. Bcl-2 blocks Bak and Bax (also Bcl2 gene family members) from activating the release of cytochrome c and the capsase Source: Modified figure from Oakes Laboratory UCSF

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Follicular lymphoma is the most common of the non-Hodgkin's lymphomas. The tumor is composed of follicle center cells, usually a mixture of cleaved follicle center cellsor small cells and large noncleaved follicle center cells, or large cells". Large cells also known as centrocytes are the majority, but small cells or centroblasts are always present. Rarely follicular lymphomas consist almost entirely of centroblasts.

A translocation between chromosome 14 and 18 has been associated with the development of Follicular lymphoma, and results in the overexpression of the bcl2 (B-cell lymphoma 2) gene. This overexpression causes a blockage of apoptosis. Bcl-2 family genes govern mitochondrial membrane permeabilisation (MMP) and can be either pro-apoptopic (i.e. Bax, Bak and Bok) or anti-apoptopic (i.e. Bcl-2, Bcl-xL, and Bcl-w). There are a total of 25 known genes in the Bcl-2 family. There are several theories concerning how the actions Bcl-2 gene family on apoptosis. Modulation of cell death may be achieved by activation or inactivation of an inner mitochondrial permeability transition (PT) pore, which is involved in the regulation of matrix Ca2+, pH, and voltage. Some Bcl-2 family proteins can induce or inhibit the release of cytochrome c in to the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Zamzami et al. (1998) related the release of cytochrome c to the actions of the PT pore on the inner mitochondrial membrane. The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane.Within the mitochondria are the caspases, the apoptogenic factors like cytochrome that if released execute apoptosis. Bcl-2 proteins either promote the escape of these factors, or keep them locked in the mitochondria. The protein Bcl-2 is an anti-apoptotic protein that resides in the outer mitochondrial membrane and the membrane of the endoplasmic reticulum. Over expression of Bcl-2 is known to block cytochrome c release, possibly through the inhibition of Bax and Bak. Bcl-2 genes have been implicated in cancer, including melanoma, breast, prostate and lung carcinomas. It is also thought to be involved in resistance to conventional cancer treatment (Bast et al., 2000). In follicular B-cell lymphoma, t(14;18) translocation which places the Bcl-2 gene next to the immunoglobulin heavy chain gene locus occurs.The Bcl-2 gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic bcl-2 protein (Vaux et al 1988). Targeted therapies are being developed. Genasense, an antisense oligonucleotide drug (G3139) has been developed to target Bcl-2. An antisense DNA or RNA strand is non-coding sequence of nucleotides, complementary to the coding strand of the target protein. An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed.It was shown that the proliferation of human lymphoma s (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. Genasense is complementary to the first 6 codons of Bcl-2 mRNA (Dias and Stein 2002). These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson 2004). There is no consensus regarding the best treatment for follicular lymphoma, conservative observation, alkylators, anthracycline regimens like. CHOP, rituximab, stem cell transplanation have all been used. The disease is generally regarded as incurablewith the exception of localised disease, which can be cured by radiation. The typical pattern is one of good responses, followed by relapse years later. Median survival is around 10 years, ranging from less than one year, to more than 20 years. Some patients may never need treatment.

References

Dias N, Stein CA. Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 2002;54:263-9. PMID 12445555.

Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681. PMID: 15902208

Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440-2. PMID: 3262202.

Mavromatis BH, Cheson BD. Novel therapies for chronic lymphocytic leukemia. Blood Rev 2004;18:137-48. PMID 15010151.

Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 1998;16:2265-82. PMID 9619836