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
Source:St. Jude Children's Research Hospital