Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Abstract

IntroductionMantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy accounting for 5% of non-Hodgkin lymphomas (NHLs). MCL arises from naive B cells (NBCs) in the mantle zone of lymph node follicles and is characterized by the t(11,14) chromosomal translocation leading to overexpression of cyclin D1 (CCND1). 1 However, murine models overexpressing CCND1 in the absence of other oncogenes, such as MYC, do not develop lymphoma, 2 implying that additional pathogenic mechanisms are involved in MCL. Cip/Kip proteins have an important role in the formation of active CDK4/cyclin D complexes. In NHLs other than MCL, p27(Kip) protein expression is inversely related to the proliferation activity of the tumors. 3 Apoptosis-related genes such as BCL2 have also been found to be altered in MCL with the use of different approaches. Homozygous deletions of BIM, a member of the BCL2 family, have also been found in MCL. 4 Epigenetic changes, such as methylation of gene promoters, have been shown to contribute to the pathogenesis of both solid and hematologic malignancies. 5 Single-locus studies analyzing methylation in MCL patient samples have shown hypermethylation of key genes, such as cell-cycle regulators p14 ARF and CDKN2A,6,7 protein phosphatase SHP-1 8 and Rho-adenosine triphosphatase PARG-1. 9 However these studies did not compare the methylation to NBCs, the normal counterparts of these malignant cells. 10 Several lines of evidence conclusively show NBCs to be the cell of origin of MCL, including immunoglobulin heavy chain mutation status, t (11,14) chromosomal breakpoint analysis, 11 and gene expression microarrays. 12,13 To develop a more comprehensive understanding of aberrant DNA methylation in MCL, we performed a genomewide analysis of MCL DNA methylation and gene expression with the use of purified normal NBCs as controls. We report that promoter DNA methylation is aberrantly distributed in the MCL genome compared with normal NBCs, and we identified aberrantly hypermethylated and hypomethylated genes that provide a basis for rational targeted therapy in this disease. Methods Patient samplesTissues and blood samples were obtained from patients newly diagnosed with MCL before any treatment after informed consent in accordance with the Declaration of Helsinki. Sample collection and laboratory studies were in compliance with institutional review board and Helsinki protocols. CD19 ϩ cells from 22 patients treated at the National Institutes of Health were purified by magnetic bead sorting from peripheral blood or pheresis products before freezing to ensure greater than 90% purity for HpaII tiny The publisher or recipient acknowledges right of the US government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accorda...

c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

“…[3][4][5][6] NOTCH1 activation may contribute to the development of other hematopoietic malignancies, including chronic lymphocytic leukemia [7][8][9] and mantle cell lymphoma. 10,11 These findings support the continued development of NOTCH inhibitors as cancer therapeutics.…”

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

“…QPCT, which encodes a glutaminyl cyclase (Fischer and Spiess, 1987;Pohl et al, 1991), is frequently methylated in malignant melanoma (Muthusamy et al, 2006). Functional PCDH8 is frequently lost in breast cancer through both mutation and promoter methylation (Yu al., 2008), and also methylated in mantle cell lymphoma (Leshchenko et al, 2010). FBN2 and the related gene FBN1 encode large modular extracellular matrix glycoproteins, which are the key components of human microfibrils (Zhang et al, 1994).…”

“…There is increasing evidence that protocadherins can function as tumour suppressors. Protocadherins 10 and 20 are epigenetically silenced in nasopharyngeal and lung cancers (Imoto et al, 2006;Ying et al, 2006), and recently it has been reported that PCDH8 is methylated in mantle cell lymphoma and breast cancer (Yu et al, 2008;Leshchenko et al, 2010). Yu et al found that reexpressing wild-type PCDH8 in a breast cancer cell line inhibited cell migration.…”

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…In that regard, chromosomal alterations and nongenetic modifications resulting in the constitutive activation of pro-oncogenic signals (for example, NF-kB, Notch, PI3K/AKT/mTOR, and Wnt) and/or deregulation of DNA repair and apoptotic pathways and genes (for example, AKT, BCL2, MCL1) have been found in subsets of MCLs, providing additional levels of plasticity in the genesis and progression of the disease. 1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common.…”

“…3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common. 3,[5][6][7]21 Short-lived response and development of resistance to first-line immunochemotherapy are major challenges in MCL and new therapeutic strategies are being developed. 1,22,23 Constitutive Wnt signaling associates to increased cellular proliferation and higher resistance to apoptosis and chemotherapy in subsets of leukemias and lymphomas and established cell lines derived from them, including MCLs.…”