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 Blood, 1 May 2006, Vol. 107, No. 9, pp. 3716-3723.
Prepublished online as a Blood First Edition Paper on January 17, 2006; DOI 10.1182/blood-2005-03-0897.

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NEOPLASIA

Gene expression and angiotropism in primary CNS lymphoma

James L. Rubenstein, Jane Fridlyand, Arthur Shen, Ken Aldape, David Ginzinger, Tracy Batchelor, Patrick Treseler, Mitchel Berger, Michael McDermott, Michael Prados, Jon Karch, Craig Okada, William Hyun, Seema Parikh, Chris Haqq, and Marc Shuman

From the Division of Hematology/Oncology, the Department of Epidemiology and Biostatistics, the Department of Pathology, and the Department of Neurosurgery, UCSF Cancer Research Institute and Comprehensive Cancer Center, San Francisco, CA; the Department of Neuropathology, M. D. Anderson Cancer Center, Houston, TX; the Department of Neurology, Massachusetts General Hospital, Boston, MA; and the Department of Veterans Affairs Medical Center, Portland, OR.

Primary CNS lymphoma is an aggressive form of non-Hodgkin lymphoma whose growth is restricted to the central nervous system. We used cDNA microarray analysis to compare the gene expression signature of primary CNS lymphomas with nodal large B-cell lymphomas. Here, we show that while individual cases of primary CNS lymphomas may be classified as germinal center B-cell, activated B-cell, or type 3 large B-cell lymphoma, brain lymphomas are distinguished from nodal large B-cell lymphomas by high expression of regulators of the unfolded protein response (UPR) signaling pathway, by the oncogenes c-Myc and Pim-1, and by distinct regulators of apoptosis. We demonstrate that interleukin-4 (IL-4) is expressed by tumor vasculature as well as by tumor cells in CNS lymphomas. We also identify high expression in CNS lymphomas of several IL-4-induced genes, including X-box binding protein 1 (XBP-1), a regulator of the UPR. In addition, we demonstrate expression of the activated form of STAT6, a mediator of IL-4 signaling, by tumor cells and tumor endothelia in CNS lymphomas. High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy.


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