Inactivation of the <i>Lamin A/C</i> Gene by CpG Island Promoter Hypermethylation in Hematologic Malignancies, and Its Association With Poor Survival in Nodal Diffuse Large B-Cell Lymphoma

Agrelo, Rubén; Setién, Fernando; Espada, Jesús; Artiga, María J.; Rodríguez, Maria E.; Pérez‐Rosado, Alberto; Sánchez-Aguilera, Abel; Fraga, Mario F.; Piris, Miguel Á.; Esteller, Manel

doi:10.1200/jco.2005.11.650

Cited by 124 publications

(110 citation statements)

References 25 publications

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“…Thus, it makes sense that the inactivation of a gene involved in ''preventing'' the aging process occurs in cancer cells. We recently found the first example of this concept: lamin A͞C (LMNA) is mutated in atypical WS, where the WRN gene is wild type (30), whereas LMNA undergoes methylation-associated silencing in hematological neoplasms (31). Here, we demonstrate that the first and paradigmatic premature aging gene, WRN, undergoes epigenetic inactivation in human cancer and can be viewed as a tumor-suppressor gene.…”

Section: Discussionmentioning

confidence: 80%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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241

227

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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Section: Discussionmentioning

confidence: 80%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

241

227

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“…Accordingly, B lymphoid cells (centrocytes and centroblasts) expressed lamin B1, whereas mantle zone lymphocytes were lamin B1 and B2 positive [14]. Cell lines derived from human neoplasms usually mirrored the lamin expression profile of the cell type they derived from [45][46][47][48].…”

Section: Discussionmentioning

confidence: 96%

Up-Regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

Bánáti¹,

Koroknai²,

Szenthe³

et al. 2017

J Microb Biochem Technol

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“…A recent study of the amounts of lamin A/C in various hematologic malignancies provided evidence for epigenetic silencing at the lamin A/C promoter region by CpG island methylation in a subset of leukemias and lymphomas. [48] There is increasing evidence that gene silencing occurs at the nuclear envelope (see recent reviews [10,13]) promoted, in part, by integral proteins of the nuclear envelope. Thus, it is tempting to speculate that increased LBR content may augment repression of the lamin A/C genes and/or facilitate sequestration of the epigenetically repressed lamin A/C genes to the peripheral nuclear heterochromatin.…”

Section: Discussionmentioning

confidence: 99%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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Objective-Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Huët anomaly (PHA) and mouse ichthyosis (ic). In this study we have utilized differentiated promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression.Materials and Methods-Wildtype (+/+), heterozygous (+/ic) and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation.Results-Wildtype (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells.Conclusions-Our observations suggest roles for LBR during granulopoiesis which may involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin and promoting down-regulation of lamin A/C expression. Category Granulopoiesis

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Inactivation of the Lamin A/C Gene by CpG Island Promoter Hypermethylation in Hematologic Malignancies, and Its Association With Poor Survival in Nodal Diffuse Large B-Cell Lymphoma

Cited by 124 publications

References 25 publications

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Up-Regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

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