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TEL2 gene cooperates with MYC gene to provoke B-cell lymphomas

The genes TEL2 and MYC cooperate with each other to promote pediatric cases of the immune system cancer B-cell lymphoma. This finding, from investigators at St. Jude Children's Research Hospital, is published in the current issue of Molecular Cell Biology (MCB).

B-cell lymphoma is a cancer in which the antibody-producing cells (B lymphocytes) multiply uncontrollably and crowd out other blood cells. The St. Jude researchers report that TEL2 cooperates with MYC to increase the chance that a certain mutation will occur in precancerous B lymphocytes, permitting these cells to become cancerous. This mutation inactivates the function of p53, a gene that orchestrates the ability of abnormal lymphocytes to commit suicide--ridding the body of potentially cancerous cells.

"The study's findings strongly suggest that physicians should look for TEL2 activity in a patient's B-cells as part of the diagnosis of B-cell lymphoma," said Gerard Grosveld, Ph.D., chair of St. Jude Genetics and Tumor Cell Biology. "TEL2 should also be considered a potential target for novel drugs to treat this disease." Grosveld is senior author of the MCB report.

The TEL2 gene is part of a family of genes called ETS transcription factors. Transcription factors prompt the cell to read the code of a specific gene and produce copies of RNA. RNA then directs the production of the protein that the gene codes for. The gene TEL1, which works to slow cell growth and multiplication, is another member of the ETS family and is a known target of mutations in human leukemia. Grosveld's group previously identified TEL2 and noted its similarity to TEL1, which prompted them to investigate whether TEL2 also played a role in leukemia. In the MCB study, the investigators discovered that, unlike TEL1, TEL2 promotes cell multiplication, playing an indirect role in the development of B lymphoma.

"TEL2 doesn't directly cause cancer," Grosveld said. "Instead, this gene promotes the development of lymphoma by enlarging the B lymphocyte population. This increases the likelihood that at least a few of the cells acquire a mutation eliminating p53 function just by chance. In the absence of p53, the cells remains alive and become cancerous."

The study's findings help explain the interlocking roles of MYC, TEL2, and p53 in the development of B lymphoma. It was already known that many human B-cell lymphomas over-express the MYC gene, either because the tumor cells acquire additional copies of this gene or because the cells suffer mutations that affect control over the level of MYC expression. Excess MYC expression spurs the cells to proliferate. This abnormal behavior then triggers p53 to instruct these overzealous cells to undergo apoptosis.

However, such rogue cells can still become fully cancerous if they succeed in eliminating p53 activity, in effect silencing the command to commit suicide. This situation occurs when increased TEL2 activity reduces the cell's ability to trigger apoptosis in response to relentless prodding by MYC to keep multiplying. As the process of apoptosis becomes sluggish, the population of B lymphocytes increases. The greater the number of these cells, the more likely some of them will eliminate their p53 function. Without the ability to commit suicide, these cells will start multiplying entirely out of control.

"This is exactly what we saw in mice that were genetically modified so their B lymphocytes were over-expressing MYC," Grosveld said. "When we forced over-expression of TEL2 in these mice, we curtailed apoptosis in the precancerous B lymphocytes that were being forced to multiply by MYC."

But even the combined effect of MYC and TEL2 wasn't enough to turn these overactive lymphocytes into lymphoma cells.

"The coup de grace consisted of a complete elimination of the apoptotic response through loss of p53 function," Grosveld said. "In fact, all TEL2/MYC B-cell lymphomas had lost their p53 functio n."

Grosveld's team found that this sequence of events modeled in the mouse also occurs in human lymphoma patients. Combined elevated TEL2 and MYC expression occurred in the B lymphocytes of over a third of patients with a B lymphoma called B-acute lymphoblastic leukemia.

"These results offer new hope for improved diagnosis," said Monica Cardone, Ph.D., a postdoctoral student in Grosveld's laboratory who did much of the work on this project. "TEL2 should be considered a new diagnostic marker, especially in patients who don't have the classic genetic mutations that physicians normally use to diagnose the disease. It will also be very interesting to study the effect of drugs that block TEL2 activity, since such an approach might one day represent an effective treatment for leukemia patients."

Other authors of the report include Ayten Kandilci, Cintia Carella, Jonas A. Nilsson, Jennifer A. Brennan, Kelli Boyd, John Cleveland (St. Jude); and Sema Sirma and Ugur Ozbek (Istanbul University).


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Source:St. Jude Children's Research Hospital


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