New key element discovered in pathogenesis of Burkitt lymphoma

August 13, 2012

Burkitt lymphoma is a malignant, fast-growing tumor that originates from a subtype of white blood cells called B lymphocytes of the immune system and often affects internal organs and the central nervous system. Now Dr. Sandrine Sander and Professor Klaus Rajewsky of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have identified a key element that transforms the immune cells into malignant lymphoma cells. They developed a mouse model that closely resembles Burkitt lymphoma in humans and that may help to test new treatment strategies (Cancer Cell).

Burkitt lymphoma typically develops in childhood and occurs most frequently in equatorial Africa and South America. This originates from germinal centers of the lymphoid organs (Peyer's patches in the small intestine, lymph nodes and spleen). The germinal center reaction is initiated by mature B cells upon detection of a foreign substance (antigen). These B cells modify their DNA in the course of the reaction, resulting finally in a highly specific antibody response against the antigen.

The B cell receptor (BCR), an antibody presented on the surface of mature B cells, plays a crucial role in the germinal center reaction. In order to optimally recognize the respective antigen and initiate an appropriate immune response, the DNA segments encoding the antibody need to be modified and rearranged. While the processes are complex, DNA breaks occur and error-prone repair mechanisms may lead to genetic mutations associated with cancer development.

It is well established that in Burkitt lymphoma, mistakes in the repair of DNA breaks result in the translocation of the c-MYC oncogene. This gene regulates cell division, and thus its expression is tightly controlled in normal cells. The c-MYC translocation leads to its deregulation, and the affected cells divide in an uncontrolled manner. However, c-MYC overexpression also leads to massive cell death. Therefore c-MYC deregulation by itself is unable to transform normal cells into cancer cells. In Burkitt lymphoma, the apoptosis induction of elevated c-MYC expression must be overcome by additional mutations preventing cell death.

Recently, Professor Rajewsky and his colleagues showed that an enzyme called PI3K is critical for the survival of mature B cells. It activates a that regulates cell growth and counteracts programmed cell death. Based on these findings Dr. Sander and Professor Rajewsky investigated an interaction of c-MYC and PI3K in mouse tumorigenesis in their present study. They demonstrated that PI3K is a key element in Burkitt lymphoma development which enables c-MYC to turn germinal center B lymphocytes into lymphoma that divide continuously and escape apoptosis.

However, not every B cell co-expressing c-MYC and PI3K transforms into a lymphoma cell, thus the researchers suspected additional genetic mutations that may play a role in Burkitt lymphomagenesis. Indeed they could identify such aberrations in their mouse model, and a study in human Burkitt lymphoma by Professor Louis Staudt (National Cancer Institute, Bethesda, Maryland, USA), which was published simultaneously in Nature (DOI: 10.1038/nature11378), confirmed these results. Staudt and colleagues showed that Burkitt lymphoma patients, besides having mutations resulting in the activation of the PI3K signaling pathway, carry genetic mutations that resemble those in the mouse.

"In addition to c-MYC deregulation, the activation of the PI3K signaling pathway is a key element in the development of Burkitt ," said Dr. Sander and Professor Rajewsky. "The inhibition of this signaling pathway could therefore be an effective strategy for treating the disease."

Explore further: Lymphoma therapy could deliver a double punch

More information: Synergy between PI3K signalling and MYC in Burkitt lymphomagenesis, Cancer Cell, 2012.

Related Stories

Lymphoma therapy could deliver a double punch

April 30, 2012
B cell lymphomas are a group of cancers of that originate in lymphoid tissue from B cells, the specialized immune cell type that produces antibodies. The development of B cell lymphoma is associated with several known genetic ...

'If Hamlet give the first or second hit': The development of Burkitt's lymphoma

November 8, 2011
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 ...

Scientists identify a critical tumor suppressor for cancer

August 2, 2012
Scientists from the Florida campus of The Scripps Research Institute have identified a protein that impairs the development and maintenance of lymphoma (cancer of the lymph nodes), but is repressed during the initial stages ...

Protein may represent a switch to turn off B cell lymphoma

May 7, 2012
Researchers studying the molecular signals that drive a specific type of lymphoma have discovered a key biological pathway leading to this type of cancer. Cancerous cells have been described as being "addicted" to certain ...

Recommended for you

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

Newest data links inflammation to chemo-brain

December 14, 2017
Inflammation in the blood plays a key role in "chemo-brain," according to a published pilot study that provides evidence for what scientists have long believed.

One in five young colon cancer patients have genetic link

December 13, 2017
As doctors grapple with increasing rates of colorectal cancers in young people, new research from the University of Michigan may offer some insight into how the disease developed and how to prevent further cancers. Researchers ...

New strategy for unleashing cancer-fighting power of p53 gene

December 13, 2017
Tumor protein p53 is one of the most critical determinants of the fate of cancer cells, as it can determine whether a cell lives or dies in response to stress. In a new study published today in the journal Nature Communications, ...

Researchers develop test that can diagnose two cancer types

December 12, 2017
A blood test using infrared spectroscopy can be used to diagnose two types of cancer, lymphoma and melanoma, according to a study led by Georgia State University.

Cancer-causing mutation suppresses immune system around tumours

December 12, 2017
Mutations in 'Ras' genes, which drive 25% of human cancers by causing tumour cells to grow, multiply and spread, can also protect cancer cells from the immune system, finds a new study from the Francis Crick Institute and ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.