Cancer Good morning ladies and gentlemen, my colleagues and I have called you in at such short notice because we need to discuss a patient who was brought to our attention earlier this week. The patient presented with rapidly progressing lymphadenopathy, subsequent examination lymph nodes congested with many small B-lymphocytes. The B-lymphocytes showed a significant chromosomal aberration in the form a 14;18 translocation. The patient has been diagnosed with lymphoma and has been prescribed an immediate course of chemotherapy. This mornings presentation will include a short description of the cell cycle and how and where certain checkpoints of genomic integrity function. My colleagues Associate Professor Cath and Dr Lucia will then explain the steps involved in contracting lymphoma with regards to the chromosomal translocation and its implications.
The cell cycle is broken functionally into 4 sections, Growth 1, Interphase, Growth 2 and the Mitotic Phase. During Interphase the cell goes about replicating DNA in preparation for Mitosis. During the Growth 2 phase the cell synthesizes the proteins and enzymes required to perform the mitotic division, as well as transporting these enzymes to their appropriate positions within the cell. The Mitotic phase is where the cell undergoes division into two separate daughter cells. The Growth 1 phase is the phase we are most concerned with; it is characterised by rapid growth and metabolic activity and a high rate of protein synthesis.
It is also the phase where oncogenic processes have their most profound effect. Late in the growth 1 is considered a point of no return within the cell cycle, because once the cell has past into Interphase, it will usually complete a successful cell division. In order to protect the integrity of the cellular genome a number of checkpoints are present which can halt the cell cycle, and if necessary, induce apoptosis. Apoptosis, or programmed cell suicide, involves the synthesis of enzymes like BAX, which bring about the death of the cell within a matter of minutes. Apoptosis is induced either when a cell is no longer required, for example extra lymphocytes formed to fight an infection once that infection has been overcome, or when irreparable damage has been detected in the genome.
To ensure there isnt random cell suicide, so-called survival genes such as BCL-2 prevent apoptosis unless a specific series of events takes place. However as you can imagine, overproduction of such a gene produces a cell of exceptional fortitude, which can make for a considerable danger if combined with certain genetic errors, as we will hear from (CATH OR LUCIA) Perhaps the most important checkpoint is the p53 protein. The gene encoding the p53 protein is the most common mutation in all human cancers. In response to genomic damage p53 binds to DNA and exerts its influence by inducing the transcription of another regulatory gene whose product binds to certain complexes required to drive the cell past the Growth 1 phase. Blocking the activity of these complexes prevents entry into interphase and therefore DNA replication. This allows time for the damage to be repaired by enzymes which may also be induced by p53.
While the precise mechanism with which p53 is alerted to the aberration remains uncertain, some aspects of the pathway are becoming clear. The Ataxia-telangiectasia mutated gene or ATM plays a role in activating p53 in response to low-level, repairable DNA damage. It is thought that (see diagram in Enoch and Norbury) cells respond to high and low levels of DNA damage differently. ie at low levels P53 is activated transiently via a direct sensor in ATM to repair the minor damage, once the repair is complete P53 goes away and the cell progresses into Interphase. If there is major DNA damage, P53 is continuously induced (in the absence of ATM) and promotes apoptosis by either directly activating death genes like BAX or by down-regulating survival genes like BCL-2.
Errors in these checkpoints often lead to conditions like the lymphoma presented in the patient in question. Dr Lucia/Cath will provide an insight into what happens when things go wrong. Science.