Blood Journal
Leading the way in experimental and clinical research in hematology

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

  1. Matthew J. Frank1,
  2. David W. Dawson1,2,
  3. Steven J. Bensinger1,3,
  4. Jason S. Hong1,
  5. Wendy M. Knosp4,
  6. Lizhong Xu5,
  7. Cynthia E. Balatoni1,
  8. Eric L. Allen1,
  9. Rhine R. Shen1,
  10. Dafna Bar-Sagi5,
  11. Gail R. Martin4, and
  12. Michael A. Teitell1,2,6
  1. 1Department of Pathology and Laboratory Medicine and
  2. 2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, and
  3. 3Institute for Molecular Medicine, University of California–Los Angeles;
  4. 4Department of Anatomy and Program in Developmental Biology, University of California at San Francisco;
  5. 5Department of Biochemistry, New York University School of Medicine, NY; and
  6. 6Molecular Biology Institute, NDC Center for Cell Control, Broad Institute for Regenerative Medicine and Stem Cell Research, and California NanoSystems Institute, University of California–Los Angeles

Abstract

B-cell lymphoma is the most common immune system malignancy. 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/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. 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.

  • Submitted May 22, 2008.
  • Accepted January 4, 2009.
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