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May 3, 2010

Scientists Implicate LTRs in the Pathogenesis of Hodgkin Lymphoma

  • Researchers in the U.K. and Germany have identified a role for long terminal repeat (LTR) stretches of DNA in the growth of Hodgkin lymphoma. They claim their studies endorse previous findings in animal studies, and may also implicate LTRs as having a causal function in other blood cancers.

    The research, by scientists at the U.K.’s University of Leeds, the Charité University Medical School, and Max Delbrück Centre for Molecular Medicine, is reported in Nature Medicine, in a paper titled, “Depression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma”.

    The work stems from the hypothesis that although LTRs derived from ancient viral infections are commonly perceived as “junk DNA” in the modern human genome, these stretches of DNA could stimulate cancer genes if not inactivated during embryonic development.

    The U.K.-German team, led by professor Constanze Bonifer, Ph.D., in Leeds and Stephan Mathas, Ph.D., at the Charité and MDC, focused on cancerous human Hodgkin/Reed-Sternberg cells (HRS). These cells are unusual in that they have largely lost expression of B cell–specific genes, they report. “This includes lack of B-cell receptor expression, which is normally required for B-cell survival, suggesting that the survival of HRS cells is regulated by different means.”

    The researchers showed that the growth of HRS lymphoma cells is instead dependent on the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). More specifically, in the Hodgkin lymphoma receptor activation was “hijacked” by the aberrantly activated LTR promoter of the MaLR family (THE1B). They also detected LTR-driven CSF1R transcripts in anaplastic large cell lymphoma (ALCL), in which CSF1R is known to be expressed aberrantly.

    LTR-driven CSF1R transcripts were absent in all of the primary samples tested from healthy donors containing various hematopoietic cell types, but were found in all tested lymph node samples from patients with Hodgkin lymphoma and in most samples from patients with ALCL. The transcripts were also undetectable in various other types of primary non-Hodgkin lymphomas, which they claim “points to the specificity of LTR-CSF1R transcripts for certain hematopoietic malignancies.”

    “We have shown this is the case in Hodgkin lymphoma, but the exact same mechanism could be involved in the development of other forms of blood cancer,” Dr. Bonifer claims. “This would have implications for diagnosis, prognosis, and therapy of these diseases.”

    The authors admit that the precise signaling pathways affected by CSF1R activation in HRS cells have yet to be identified. However, they suggest, “The observations that CSF1R is constitutively activated in most Hodgkin lymphoma–derived cell lines, that all primary Hodgkin lymphoma cells express CSF1R and CSF-1, and that cell lines with CSF1R activation are sensitive to its inhibition, all point toward CSF1R signaling as a new therapeutic target for the treatment of Hodgkin lymphoma.”

    The presence of the transcripts may also be useful for diagnostic and prognostic purposes, they suggest, including the detection of minimal residual disease in Hodgkin lymphoma. “Our detection of LTR-CSF1R transcripts also in anaplastic large cell lymphoma suggests that the activation of usually silenced repeat elements has a driving role in the pathogenesis of several human malignancies,” they conclude. “Furthermore, LTR depression might also contribute to the aberrant CSF1R expression that has been described in nonhematological malignancies.”


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