Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas
- 12 March 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 113 (11), 2478-2487
- https://doi.org/10.1182/blood-2008-05-156943
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.This publication has 59 references indexed in Scilit:
- Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomasOncogene, 2008
- Sprouty proteins, masterminds of receptor tyrosine kinase signalingAngiogenesis, 2008
- Evidence That Sprouty 2 Is Necessary for Sarcoma Formation by H-Ras Oncogene-transformed Human FibroblastsOnline Journal of Public Health Informatics, 2008
- Bethesda proposals for classification of lymphoid neoplasms in miceBlood, 2002
- Restriction landmark genome scanningMethods, 2002
- ERK Pathway Positively Regulates the Expression of Sprouty GenesBiochemical and Biophysical Research Communications, 2001
- TCL1 Oncogene Expression in B Cell Subsets from Lymphoid Hyperplasia and Distinct Classes of B Cell LymphomaLaboratory Investigation, 2001
- Inhibition of the MEK/ERK Signaling Pathway Blocks a Subset of B Cell Responses to AntigenThe Journal of Immunology, 2001
- Mammalian Sprouty-1 and -2 Are Membrane-Anchored Phosphoprotein Inhibitors of Growth Factor Signaling in Endothelial CellsThe Journal of cell biology, 2001
- Aberrant CpG-island methylation has non-random and tumour-type–specific patternsNature Genetics, 2000