Boston researchers pinpoint IgH 3’ regulatory region as a target for lymphoma therapy

Individuals who do damage to people’s lives from a far-removed position are difficult to counteract, whether they are snipers or criminals hiding behind multiple levels of intermediaries and lackeys. The same can be true in various biological processes, where potential targets for therapy may be far removed from the point of the visible biological effects. But any “bad actor” can be tracked down, and researchers at the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children’s Hospital Boston may have done just that for one of the possible villains involved in B-cell lyphomas, including Burkitt’s lymphoma, an aggressive cancer in children.

Jeffrey Bouley
BOSTON—Individuals who do damage to people's lives from afar-removed position are difficult to counteract, whether they are snipers orcriminals hiding behind multiple levels of intermediaries and lackeys. The samecan be true in various biological processes, where potential targets fortherapy may be far removed from the point of the visible biological effects.But any "bad actor" can be tracked down, and researchers at the Program inCellular and Molecular Medicine and the Immune Disease Institute (PCMM/IDI) atChildren's Hospital Boston may have done just that for one of the possiblevillains involved in B-cell lyphomas, including Burkitt's lymphoma, anaggressive cancer in children.
 
Their findings may bode well, too, for victims of multiplemyelomas and other blood-related cancers.
 
 
The link that the researchers describe in the article"Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3'Regulatory Region," published in the Dec. 10 issue of Nature, is between acommon mutation that can lead to cancer, and a distant gene regulator thatenhances its activity.
 
B cells produce antibodies to help fight infections, butthey can become cancerous should a gene known as c-myc leap to the IgH regionof DNA—responsible for building antibodies—fuses with it and becomesover-activated.
 
For some years now, researchers have been stumped as to howthis occurs and what components in the IgH region actually active c-myc, notesDr. Frederick Alt, the scientific director of PCMM/IDI, an investigator of theHoward Hughes Medical Institute and senior author of the Nature-publishedstudy.
 
"IgH-to-myc translocation is the classic example ofactivation of an oncogene in cancer," Alt says. "But nobody really understoodhow it works."
 
Now, though, he says that he and his colleagues haveidentified the key regulatory component, achieving for the first time anunderstanding how this chromosomal translocation "hijacks a B cell's operationbadly enough to lead to cancer."
 
 
As the PCMM/IDI noted in a recent news release about theresearch, aberrant DNA translocations can occur during two different stages ofa B cell's development: during a process known as VDJ recombination, when aprogenitor B cell creates an antibody to fight a specific pathogen, or duringclass switch recombination, when a mature B cell gives its antibody a differentstrategy to fight infection (changing from an IgM to an IgG antibody, for example).
 
 
Alt and his PCMM/IDI colleagues had done past research thatshowed a specific part of the IgH region called IgH 3' regulatory region(IgH3'RR) was a "far-reaching gene regulator" that enhanced the transcriptionof neighboring genes in the IgH region during class switch recombination. Basedon this, they concluded that they should probably focus on IgH3'RR and see whatthey found.
 
Led by Alt and Dr. Monica Gostissa of PCMM/IDI, who servedas first author for the published study, the team decided to investigate therelationship between IgH3'RR and lymphoma by deleting IgH3'RR in a line ofmutant mice previously generated in Alt's lab. These mice routinely develop aB-cell lymphoma in which c-myc is translocated to the IgH region of the DNA.However, without IgH3'RR, mature B cells did not become cancerous, suggestingthat mature B cells—from which most human lymphomas originate—need IgH3'RR inorder to develop into lymphoma.
 
"The study shows that the IgH3'RR is a key element forturning on the cancer-causing activity of c-myc after it is translocated to theIgH locus," Alt says, noting that the research team found that thecancer-causing activity of the IgH3'RR on c-myc can extend over surprisinglylong chromosomal distances.
 
 
The research work suggests that IgH3'RR is a promising newtarget for arresting lymphomas and other blood-related cancers that arise frommature B cells, Gostissa says.
 
 
However, while the team's findings define a major oncogenicrole for IgH3'RR in activating c-myc subsequent to IgH/c-myc translocations,they did note in the Nature article that "we do not rule out an additional rolein promoting translocations by enhancing [activation induced cytidinedeaminase]-mediated lesions in certain S regions regulated by this element."
 
 
Although their findings indicate IgH3'RR is a promisingtarget, there is already one clear downside of therapy aimed in that direction.As Gostissa acknowledges, inactivating IgH3'RR could impair the B cells'versatility in creating different classes of antibodies. On the other hand, shenotes, it would not leave a patient totally immune-deficient because the Bcells would at least retain some of their activity.
 
Also, a treatment such as this would be reversible, Gostissaadds, thus the B cell "versatility" could theoretically be restored later.
 
 
As they move forward with further research in this area, theresearchers will next investigate what exactly happens to tumors when IgH3'RRis eliminated. Then they will create a cell-based drug screening assay to testfor possible IgH3'RR inhibitors.

The study was funded by grants from the National Institutesof Health and the Leukemia and Lymphoma Society of America.

Jeffrey Bouley

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