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

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 Bcell tumors to discover tumor-associated IntroductionHyperactivation of the RAS-RAF-MEK-ERK signaling pathway (MAPK-ERK pathway) promotes a variety of cancers, including hematologic malignancies, by enhancing cell proliferation and cell survival and by affecting differentiation. 1,2 The MAPK-ERK pathway can be constitutively activated by tumor type-specific gain-of-function mutations in (or overexpression of) upstream pathway members, such as growth factor receptors, RAS, and RAF, and by loss-of-function mutations in (or repression of) negative pathway regulators, such as NF1, SPROUTY, or SPRED proteins. 3 Ectopic expression of T-cell leukemia 1 (TCL1), a gene that encodes a 14-kDa protein that augments AKT pathway signaling in lymphocytes, is common in mature B-cell leukemias and lymphomas. [4][5][6] A causative role for ectopic TCL1 expression in lymphocyte transformation is supported by the observation that a spectrum of Tand B-cell tumors form in TCL1 transgenic (TCL1-tg) mice, in which the human TCL1 gene is ectopically expressed under the control of an E-B29 promoter in mature lymphocytes. 7 The mechanism(s) by which ectopic TCL1 expression promotes T and B lymphocyte transformation is not fully understood. In T cells, TCL1 augments AKT and MAPK-ERK signaling with each pathway independently contributing to increase T-cell proliferation in TCL1-tg mice. 8 There is also evidence that the tumorigenic activity of TCL1 involves more than augmentation of AKT signaling because it has been shown that increasing AKT activity in B cells to levels higher than are detected in TCL1-tg B cells by deleting Pten, a negative regulator of AKT, fails to cause lymphocyte transformation. 9 Moreover, it is not known what effect TCL1 has on MAPK-ERK signaling in B cells. The observation that in humans and TCL1-tg mice there is a long latency before B-and T-cell tumors form after ectopic expression of TCL1 is consistent with the conclusion that additional changes beyond TCL1-mediated augmentation of AKT signaling are needed to transform lymphocytes.Because TCL1 expression is more frequently dysregulated in B-cell compared with T-cell tumors, we have focused on its role in B-cell malignancies. B-cell lymphomas from TCL1-tg mice display aneuploidy and chromosomal translocations. In many of these lymphomas, trisomy 15 and its associated c-MYC overexpression results in a lesion that histologically and molecularly resembles human Burkitt lymphoma (BL). 10,11 In addition to genetic alterations, TCL1-tg B-cell tumors also display reproducible genomewide p...

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

“…This contrasts with the proposed tumour suppressor activity of SPRY2 in breast, prostate and lung cancer on the basis of its decreased expression, as compared with normal tissue (McKie et al, 2005;Fong et al, 2006;Lo et al, 2006;Sa´nchez et al, 2008;Frank et al, 2009). Concordantly with our results, a meta-analysis of data available at the Oncomine database supports that SPRY2 expression is higher in colon …”

“…SPRY2 expression in human cancers depends on tumour type. SPRY2 is downregulated in breast, prostate, and liver tumours and in B-cell diffuse lymphoma, which would suggest a tumour suppressive role (McKie et al, 2005;Fong et al, 2006;Lo et al, 2006;Sa´nchez et al, 2008;Frank et al, 2009). In contrast, SPRY2 is upregulated in melanoma cell lines concomitantly to mutation of N-RAS and B-RAF (Tsavachidou et al, 2004;Bloethner et al, 2005).…”

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

“…Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with either elevation of systemic TSH levels or increased activation of the ERK MAPK pathway.…”

“…Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.…”

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

“…This observation confirms that this variant is extremely rare/private. A direct analysis of the SPRY2 cDNA extracted from the LCLs confirmed that this gene is expressed in B cells 14 and the T355 allele is present in transcripts from LCLII7 (data not shown). The same finding was obtained on RNA freshly extracted from white blood cells from individuals II-10, II-7, III-24 and III-26 (data not shown).…”