Blood cancers may be caused by inactivation of a "tumor suppressor" gene

Apr 25 2006

Inactivation of a "tumor suppressor" gene could be a major cause of a class of blood cancers called diffuse large B-cell lymphomas, reports a team of researchers at the Weill Medical College of Cornell University.

The discovery of the gene, called PRDM1, as a tumor suppressor sheds new light on the cause - and possible treatment - of diffuse large B-cell lymphomas (DLBCLs), a cancer of the blood's B-lymphocytes. DLBCLs comprise about 30 percent of non-Hodgkin's lymphomas.

"This explains a lot of the biology of DLBCLs. When this gene is abnormally switched off, mature B cells get stuck in a loop where they proliferate and fail to differentiate and die as they should," explains lead researcher Dr. Wayne Tam, Assistant Professor of Pathology and Laboratory Medicine at Weill Cornell Medical College, and Assistant Attending Pathologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City.

His team recently reported their findings online in the journal Blood, and they will be published in print in the May issue.

DLBCL is the most common of the non-Hodgkin's lymphomas. They tend to be aggressive and usually require prompt treatment. Fortunately, available chemotherapies can cure, or at least control, the disease for many patients. The exact causes of DLBCLs have remained a mystery.

However, part of that mystery may have been solved with the discovery of genetic abnormalities in PRDM1.

"Cancer researchers have long known that certain genes work to suppress the out-of-control proliferation of new cells -- these genes are called 'tumor-suppressors.' Lymphoma researchers have been looking for a while for this type of gene with respect to DLBCLs," explains study senior author Dr. Daniel M. Knowles, Professor and Chairman of the Department of Pathology and Laboratory Medicine at Weill Cornell.

The Weill Cornell team looked specifically at human chromosome 6q21, a known locus for tumor suppression in large-cell lymphomas.

They narrowed their search to PRDM1, which plays a key role in the life cycle of B lymphocytes.

"Normal B cells mature in the bone marrow, then migrate to the lymph nodes," Dr. Tam explains. "There they proliferate in what are known as the 'germinal centers.' If all goes well, many of these lymphocytes end up maturing through a process called 'terminal differentiation' into full-grown plasma cells. Those plasma cells then go out into the body to fulfill their role and die out naturally."

In cell culture studies, adding active, over-expressed PRDM1 pushed cells to differentiate into plasma cells. "That confirmed to us that this gene is what we call a 'master regulator' of this process," Dr. Knowles says.

On the other hand, mice genetically engineered to lack active PRDM1 "didn't end up having plasma cells at all," he notes.

"This critical function of PRDM1 in plasma cell differentiation strongly suggests that at least some DLBCLs arise because normal terminal differentiation into plasma cells is blocked through inactivation of the PRDM1 gene," Dr. Tam says. Inactivating PRDM1 may keep the B-cells "locked" in a cancer-like state where they proliferate uncontrollably in the germinal center, without ever maturing into plasma cells.

He adds that PRDM1 fits the classic tumor-suppressor model because both of its gene copies ("alleles") need to be knocked out to render it completely inactive. "And in many DLBCLs we see exactly that - a deletion on one allele and also a mutation in the other. It fits the classic 'two-hit' model," Dr. Tam says.

So what does all this mean to patients battling DLBCLs? Right now, the research is still at the level of basic science. However, "if we can find a means of restoring this disabled terminal differentiation pathway, that could prove a major advance in treating this disease," according to Dr. Knowles.

The researchers noted that active PRDM1 may have tumor-suppressing effects on other key genes, as well.

"There are several other very promising downstream targets," Dr. Tam notes. "Each might someday prove to be a potent weapon against this cancer."

http://www.med.cornell.edu/