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Aug 30, 2007

Scientists Elucidate Pathway for Lymphoma Growth

  • A group of researchers discovered the molecular process by which the PAX5 protein, necessary for lymphocyte development, promotes the growth of common lymphomas.

    “We have long believed that PAX5 was involved in B-lymphomagenesis, based on the discovery of PAX5-specific translocations and somatic hypermutations in diffuse large B cell and other non-Hodgkin lymphomas,” comments Andrei Thomas-Tikhonenko, Ph.D., an associate professor in the department of pathobiology in the school of veterinary medicine at the University of Pennsylvania. “Yet at the molecular and cellular levels, the contribution of PAX5 to neoplastic growth remained undeciphered.”

    The study used two B cell lymphoma cell lines that spontaneously silence PAX5 and then form slow-growing tumors. The researchers reconstituted these cells with an engineered version of PAX5 that required the synthetic estrogen tamoxifen for activity. In the experiment, tumors grew briskly when mice were treated with tamoxifen but stagnated if tamoxifen were withheld.

    After large-scale gene-profiling studies, the team found “that PAX5, which regulates gene expression, instructs B cells to make enough of the components of B cell receptors to spur tumor growth even in the absence of foreign antigens, which normally initiate the immune response,” reports Dr. Thomas-Tikhonenko.

    Studies on human clinical samples corroborated this conclusion, he adds. Approximately half the lymphoma samples from the University of Oxford’s John Radcliffe Hospital tumor bank exhibited evidence of abnormal B-cell receptor activation.
    UPenn researchers collaborated with the Wistar Institute and University of Oxford on this study.

    The findings will be published in the September issue of The Journal of Clinical Investigation.



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