Hlady R.A.,Eppley Institute for Research in Cancer and Allied Diseases |
Novakova S.,Eppley Institute for Research in Cancer and Allied Diseases |
Opavska J.,Eppley Institute for Research in Cancer and Allied Diseases |
Klinkebiel D.,University of Nebraska Medical Center |
And 18 more authors.
Journal of Clinical Investigation | Year: 2012
DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b -/- lymphomas, but not in Dnmt3b -/- pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b -/- lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b +/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies.
Iqbal J.,University of Nebraska Medical Center |
Wilcox R.,University of Michigan |
Naushad H.,University of Nebraska Medical Center |
Rohr J.,University of Nebraska Medical Center |
And 9 more authors.
Blood Reviews | Year: 2016
The novel genetic information gained from genome-wide high throughput techniques has greatly improved our understanding of peripheral T-cell lymphoma (PTCL). PTCL consists of numerous distinct entities and is currently diagnosed using a combination of clinical and morphologic features and immunophenotyping together with limited molecular assays leading to an often fragmented, complicated diagnostic system. The diagnosis of many cases is challenging even for expert hematopathologists and more than a third of the cases cannot be further classified and thus put into the PTCL-NOS category. Gene expression profiling (GEP) has significantly improved the molecular classification of PTCLs and identified robust molecular signatures for common nodal subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), anaplastic T-cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL) and extra-nodal NK/T cell lymphoma (ENKTL). These studies also led to identification of novel molecular subtypes with distinct prognosis, that otherwise could not be identified by conventional methods. Integration of massive sequencing strategies and gene expression has characterized driver genetic alterations in common subtypes like AITL, ALCL, ENKTL and other PTCLs. These studies have identified oncogenic pathways and genes affected in specific disease subtypes that can be potentially targeted by specific therapies. Novel treatment options with FDA approved drugs directed towards mutant IDH2, the NF-κB, JAK/STAT, or mTOR pathways illustrate the usefulness of genome-wide techniques to identify targets for therapy. In this review, we highlight recent advances in the molecular diagnosis and prognosis of PTCL using these genome-wide techniques. © 2015.