Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cellspecific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL.cancer genetics ͉ signal transduction ͉ nuclear architecture ͉ lymphomatoid papulosis B alanced chromosomal translocations are a hallmark of cancer cells, and are thought to be important, if not causal, for hematopoietic and mesenchymal tumorigenesis (1). At the molecular level, translocations generally result in either altered expression of genes located directly at a breakpoint, or in fusion of genes located at the 2 breakpoints (1). In most cases, the affected genes are transcription factors or tyrosine kinases, and the translocation generally leads to their inactivation or constitutive activation. This defect often causes inhibition of differentiation or uncontrolled proliferation. Nevertheless, translocations are, at least in some cases, not sufficient to fully transform cells, because chromosomal disease-associated translocations are present in healthy individuals (2), and transgenic mice expressing known tumor fusion proteins do not spontaneously develop tumors in most cases (1, 2).The translocation t(2;5)(p23;q35) is characteristic for anaplastic large cell lymphoma (ALCL), a subgroup of peripheral T cell lymphomas (TCL) (3, 4). By fusion of the 5Ј oligomerization domain of the nucleophosmin (NPM1) gene (located on 5q35) with the 3Ј anaplastic lymphoma kinase (ALK) tyrosine kinase domain (2p23), this translocation results in a NPM-ALK fusion protein with constitutive activation of the ALK kinase (3). Several questions regarding the pathogenesis of ALCL are unresolved. First, in Ϸ40% of systemic ALCL, the translocation t(2;5) is not present (4), suggesting yet unknown alternative mechanisms of transformation. Second, the expression of NPM-ALK per se might not be sufficient for malignant transformation to ALC...