'If Hamlet give the first or second hit': The development of Burkitt's lymphoma
The human c-myc gene encodes a transcription factor (MYC) involved in the regulation of a vast number of other genes it has been estimated that the transcription of about one in six genes is somehow under the control of MYC. Perhaps because of MYC's wide range of targets, mutations of the c-myc gene are frequently associated with a variety of tumours, not only with Burkitt's lymphoma. Mutations that lead to excessive amounts of the MYC protein are particularly threatening.
It has long been known that Burkitt's lymphoma only develops when MYC is mutated or overexpressed, although experiments in mice have shown that some animals live quite happily and healthily with higher levels of the MYC protein. This observation is consistent with the "second hit" model for the origin of cancer: as well as a change to c-myc, a second gene must also be disturbed before disease is initiated. In the case of lymphomas, the second hit is often in the p53 or the Bcl2 gene. Loss of p53 or increased amounts of the BCL2 protein are both associated with lymphoma. But how does the course of the disease relate to the nature of the second hit?
This question has now been investigated by Sexl's and Stoiber's groups. Using a mouse model of human lymphoma, the scientists compared the effects on the immune system of deleting the p53 gene or over-activating the Bcl2 gene, or both. The results were dramatic. If the p53 gene was mutated, the resulting tumours were no longer recognized and killed by the mouse's immune system. In other words, such tumours escaped the mouse's normal "surveillance" mechanism and went on to cause full-blown lymphoma. On the other hand, if instead the Bcl2 gene was overexpressed (to produce more BCL2 protein), the mouse's immune system could recognize and attack the tumour cells, thereby slowing or preventing cancer development. If both the p53 and the Bcl2 genes were affected, immune recognition remained efficient, in other words the Bcl2 effect is dominant.
The results show for the first time that the nature of the "second hit" determines whether the animals are able to mount an immune response against the developing lymphoma. Interestingly, Sexl's collaboration partner Ulrich Jäger from the Medical University of Vienna has obtained preliminary data from human patients that are consistent with the results in mice. The collaboration shows once again the value of comparative medicine in understanding the progression of human diseases.
The findings have extremely important consequences for tumour therapy in humans. First, because of the association of high BCL2 levels with tumour development, a number of pharmaceutical companies are currently developing BCL2 inhibitors for use in cancer therapy. As Sexl points out, though, "The inhibitors may have the unwanted effect of preventing the natural immune reaction. It will be important to evaluate the consequences of BCL2 inhibition carefully taking the host immune system fully into account to ensure that the drugs have no harmful side-effects." Secondly, the results may potentially shape future immunotherapeutic approaches, as whether a tumour overexpresses Bcl2 or does not express p53 clearly has a dramatic influence on the course of disease.
More information: The paper, "The cooperating mutation or 'second hit'" determines the immunologic visibility toward MYC-induced murine lymphomas," by Christian Schuster, Angelika Berger, Maria A. Hoelzl, Eva M . Putz, Anna Frenzel, Olivia Simma, Nadine Moritz, Andrea Hoelbl, Boris Kovacic, Michael Freissmuth, Mathias Müller, Andreas Villunger, Leonard Müllauer, Ana-lris Schmatz, Berthold Streubel, Edit Porpaczy, Ulrich Jäger, Dagma Stoiber and Veronika Sexl is published in the current issue of the journal Blood (2011, 118(17):4635-45).
Provided by University of Veterinary Medicine -- Vienna
- Silencing small but mighty cancer inhibitors Dec 10, 2007 | not rated yet | 0
- An enzyme that mutates antibodies also targets a cancer-causing oncogene Dec 11, 2008 | not rated yet | 0
- Protein may help diagnose and treat lymphoma in people and dogs Jul 14, 2011 | not rated yet | 0
- Researchers zero in on the tiniest members in the war on cancer Dec 13, 2007 | not rated yet | 0
- You can teach an old dog new tricks: anti-malarial prevents cancer in mice Dec 21, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer 3 hours ago | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer 3 hours ago | not rated yet | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 6 hours ago | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 7 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 7 hours ago | 5 / 5 (3) | 0
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
1 hour ago | 5 / 5 (1) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
1 hour ago | not rated yet | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
7 hours ago | 5 / 5 (3) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
4 hours ago | 5 / 5 (1) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
4 hours ago | 5 / 5 (2) | 0 |
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
22 hours ago | 4.9 / 5 (9) | 0 |