Abstract
Clinical heterogeneity is a major barrier to effective treatment of chronic lymphocytic leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-Erk) signaling plays a role in the heterogeneous clinical outcome of CLL patients. In this study, we have investigated the role of Sprouty (SPRY)2 as a negative regulator of receptor and nonreceptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor-prognosis patients compared with those from good-prognosis patients. Overexpression of SPRY2 in CLL cells from poor-prognosis patients increased their apoptosis. Conversely, downregulation of SPRY2 in CLL cells from good-prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell-specific transgenic overexpression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the B-cell receptor (BCR) and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF, and spleen tyrosine kinase (SYK) in normal B cells and CLL cells. We also show that SPRY2 is targeted by microRNA-21, which in turn leads to increased activity of Syk and Erk in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of CLL.
Original language | English (US) |
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Pages (from-to) | 2310-2321 |
Number of pages | 12 |
Journal | Blood |
Volume | 127 |
Issue number | 19 |
DOIs | |
State | Published - May 12 2016 |
Funding
The authors thank Dr Gail R. Martin for donating the Spry2(tg) mouse strain to the Mutant Mouse Regional Resource Center, and the UNMC Flow Core facility. This work was supported by grants from the Department of Genetics, Cell Biology and Anatomy (UNMC); pilot grant funds from Dr Vimla Band; funding from Dr Robert T. Binhammer; grants from the National Institutes of Health, National Cancer Institute (CA87986 and CA105489) (H.B.); and graduate research assistance by UNMC (A.S.).
ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology