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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2478-2487.
Prepublished online as a Blood First Edition Paper on January 15, 2009; DOI 10.1182/blood-2008-05-156943.
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Submitted May 22, 2008
Accepted January 4, 2009
Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas
Matthew J. Frank, David W. Dawson, Steven J. Bensinger, Jason S. Hong, Wendy M. Knosp, Lizhong Xu, Cynthia E. Balatoni, Eric L. Allen, Rhine R. Shen, Dafna Bar-Sagi, Gail R. Martin, and Michael A. Teitell*
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Institute for Molecular Medicine, University of California at Los Angeles, Los Angeles, CA, United States
Department of Anatomy and Program in Developmental Biology, University of California at San Francisco, San Francisco, CA, United States
Department of Biochemistry, New York University School of Medicine, New York, NY, United States
Molecular Biology Institute, NDC Center for Cell Control, Broad Institute for Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, United States
* Corresponding author; email: mteitell{at}ucla.edu.
B-cell lymphoma is the most common immune system malignancy. Over-expression or ectopic expression of BCL2, BCL6, MYC, TCL1 and other tumor-promoting genes underlie B-cell transformation. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B-cells by CD40/BCR co-stimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability, effects opposite of those caused by ectopic TCL1 expression. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling.
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