NEW YORK (GenomeWeb News) – An international team led by investigators at the National Institutes of Health has identified new pathogenic pathways in a form of non-Hodgkin's lymphoma called Burkitt lymphoma, including some containing potential treatment targets.
"By merging functional and structural genomic data we have uncovered previously unappreciated pathways in [Bukitt lymphoma] pathogenesis, several of which are amenable to therapeutic attack," National Cancer Institute senior investigator Louis Staudt, the study's senior author, and colleagues wrote in a study online yesterday in Nature.
Staudt and his colleagues looked for recurrently altered genes and pathways by comparing new RNA sequence data for sporadic Burkitt lymphoma tumors and cell lines with existing sequence information on another type of lymphoma called diffuse large B-cell lymphoma, or DLBCL, that's thought to spring from the same B cell source as Burkitt lymphoma.
Two pathways in particular stood out in the analysis and in the team's follow up experiments. One contained a transcription factor encoded by TCF3 that regulates the B-cell receptor, or BCR, contributing to so-called "tonic" BCR signaling through the phosphoinositide 3 (PI3) kinase pathway. The other involved cyclin D3 isoforms that helps regulate progression through cell cycle.
"Hopefully, the new insights into [Burkitt lymphoma] pathogenesis … will prompt clinical evaluation of drugs targeting the PI3 kinase pathway, tonic BCR signaling, and cyclin D3/CDK6 in [Burkitt lymphoma]," researchers wrote. "Eventually, the rational combination of such targeted agents could provide more effective and less-toxic treatments of [Burkitt lymphoma] worldwide."
Previous research has shown that some Burkitt lymphoma sub-types are linked to Epstein-Barr virus or HIV infections, while other cases spring up sporadically, the study authors explained, though more research is needed to understand how the cancer-causing pathways found in each sub-type compare with one another and to those that are active in DLBCL.
Moreover, although aggressive chemotherapy appears to be an effective treatment for some individuals with Burkitt lymphoma, that approach is not always feasible or effective, prompting researchers to search for new treatment options.
"Whereas high-dose chemotherapy can often cure [Burkitt lymphoma] in younger patients from developed countries, these regimens are unsafe in older patients and cannot be deployed in less developed regions due to immune suppression and to logistical difficulties that preclude effective delivery," researchers wrote.
In an effort to find new mutations that might serve as targets for future treatment development, researchers used the Illumina HiSeq 2000 to sequence RNA from 28 Burkitt lymphoma tumors and 13 Burkitt lymphoma cell lines.
They then compared these to existing RNA sequence data for 80 diffuse large B-cell lymphomas (52 classified as germinal centre B-cell-like DLBCL and 28 activated B-cell-like DLBCL samples), looking for mutations that were found more often in Burkitt lymphomas than in the DLBCL samples.
As shown previously, researchers saw that MYC gene mutations were a far more common feature of Burkitt lymphoma than of DLBCL. Likewise, the DLBCL samples harbored many recurrent mutations not present in the Burkitt lymphomas, supporting the notion that the two types of B-cell cancer are genetically separate entities.
Among the recurrently mutated Burkitt lymphoma genes were TCF3 and its regulator ID3, the team reported, with some 70 percent of sporadic Burkitt lymphoma cases carrying alterations to one or both genes. Recurrent alterations in TCF3 and ID3 also turned up in HIV- and Epstein-Barr virus-associated Burkitt lymphoma samples, but at somewhat lower rates.
In addition, almost 40 percent of the sporadic Burkitt lymphoma samples contained mutations expected to spur on a cell cycle progression pathway regulated by the CCND3 gene product, cyclin D3.
Through a series of follow-up experiments that included RNA interference screens and other cell line studies, the researchers delved into the functional consequences of altering the TCF3/ID3 and CCND3 pathways, uncovering some downstream players influenced by these recurrently mutated genes.
They also began looking at potential treatment targets in those pathways. In a mouse xenograft model, for instance, the investigators were able to curb and reverse Burkitt lymphoma tumor growth by inhibiting a component of the cell cycle progression pathway that becomes overactive in the presence of Burkitt lymphoma-associated CCND3 mutations.