Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.

Follicular lymphoma (FL) is an incurable malignancy1, with transformation to an aggressive subtype being a critical event during disease progression. Here we performed whole genome or exome sequencing on 10 FL-transformed FL pairs, followed by deep sequencing of 28 genes in an extension cohort and report the key events and evolutionary processes governing initiation and transformation. Tumor evolution occurred through either a ‘rich’ or ‘sparse’ ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histones, JAK-STAT signaling, NF-κB signaling and B-cell development genes. Longitudinal analyses revealed chromatin regulators (CREBBP, EZH2 and MLL2) as early driver genes, whilst mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides novel insights into the genetic basis of follicular lymphoma, the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations within the CPC represents an attractive therapeutic strategy.

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Key Points• EZH2 mutations occur in more than 25% of follicular lymphoma patients.• Mutations predominantly represent an early/clonal event in the pathogenesis of the disease.Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n 5 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n 5 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy. (Blood. 2013; 122(18):3165-3168) Introduction Next-generation sequencing (NGS) studies have shown frequent mutations in epigenetic regulators in almost all cases of follicular lymphoma (FL).1,2 These include EZH2, the catalytic subunit of PRC2, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), a repressive chromatin mark.3 Somatic gain-of-function mutations of EZH2 at codon Y646 (previously Y641) were identified in 7% to 22% of FLs and germinal center B-cell type diffuse large B-cell lymphomas leading to elevated H3K27 trimethylation [4][5][6][7][8] with mutations at codons A682 and A692 described in isolated cases of diffuse large B-cell lymphomas. 2,9-11 As highly selective EZH2 inhibitors have now been developed, [12][13][14] we set out to assess EZH2 mutation status, the effect of mutations on global gene expression, and the clonal representation of EZH2 mutations as the disease progresses. Study design Patient samplesGenomic DNA from 181 diagnostic FL patients with accompanying clinical and gene expression data 15 were obtained through the Lymphoma/Leukemia Molecular Profiling Project consortium. DNA from 185 additional FL patients (56 obtained at diagnosis and 129 at relapse) and 33 paired FL and transformed FL (tFL) samples were sourced from the tissue archive at the Barts Cancer 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 accordance with 18 USC section 1734.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.BLOOD, 31 OCTOBER 2013 x VOLUME 122, NUMBER 18 3165For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Institute. The study was approved by the London Research Ethical Committee (05/Q0605/140) and was conducted in accordance with the...

Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1(-/-) cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1(-/-) cells. MLL-AF9 could not initiate leukemia in Bmi1(-/-)Hoxa9(-/-) mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16(Ink4a)/p19(ARF) locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.

The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16 INK4a as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16 INK4a transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16 INK4a . Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16 INK4a . Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16 INK4a . Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

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Measles is an acute viral infectious disease caused by an RNA-containing virus of Morbilliviridae genus. This infectious disease is characterized by the development of catarrhal syndrome, general intoxication syndrome and specific exanthema. The virus is transmitted from person to person by airborne mechanism, when coughing, sneezing and exhaling air droplets during conversation. It is shown that measles is characterized by long-term immunosuppression, which persists for a long period after the patient's clinical recovery and normalization of blood parameters that can lead to an exacerbation of various chronic and autoimmune diseases. Taking into account the impairment of cytokine and immunological reactivity observed in adult patients with measles infection, violations of the dynamics of interferon levels elevation and immunosuppression caused by the virus itself, as well as the lack of studies on autoantibody levels in patients with measles of varying severity, investigating autoimmune markers is of great relevance as can be used to predict and prevent the development and activation of autoimmune responses. The purpose of the study is to determine the involvement of autoimmune reactions in the immunopathogenesis of measles infection in individuals with various degrees of severity of the disease. The study included 65 patients with a diagnosis of measles who were treated at the Kharkiv region clinical infectious hospital in the period for 2017 – 2019. Depending on the severity of the disease and the presence of complications the patients included in the study were divided into 4 groups. The control group consisted of 20 voluntary donors who at the time of blood sampling had no clinical signs of measles, had no contact with infected patients, and had no exclusion criteria. All patients included in the study were tested for serum levels of antibodies to cell membrane phospholipids, IgG to liver and kidney microsomes (anti-LKM-1), and IgG to native DNA (ADNA 2) on the 1st and 10th day of hospital stay. These indicators were assessed by the method of solid-phase enzyme immunoassay (ELISA) using test systems manufactured by “Granum” LLC (Ukraine), EUROIMMUNE (Germany) and BioRad (USA). Statistical processing of the obtained results was carried out using the Statistica 6.0 software. When interpreting the significance of the difference in results, the Student's criterion was used; the critical value of the significance level was considered to be p ˂ 0.05. Results and discussion. It was found that on the day of admission to the hospital there was an increase in the level of autoantibodies to native DNA, liver and kidney microsomes, as well as cell membrane phospholipids in all groups of patients. In dynamics (on the 10th day of hospital stay), the patients of groups 1-4 demonstrated a decrease in the level of all types of autoantibodies; in the patients who had a severe course of the disease and developed complications development, the levels was higher than in the control group. The obtained data indicate that with the development of measles infection against the background of activation of general and specific immune response, there is an activation of autoimmune reactions, whose activity fades as the infectious process goes away. Autoimmune reactions under a favourable clinical course of measles infection, most likely, are not aggressive but protective by their nature and are aimed at eliminating infected and damaged cells. Patients with measles of varying severity have increased levels of autoantibodies to native DNA, liver and kidney microsomes, as well as cell membrane phospholipids. It has been found out that the levels of autoantibodies do not go beyond the reference values, but in severe disease, borderline values of autoantibodies are recorded in a significant number of patients. The study of autoantibody levels can be recommended in cases of severe measles infection, both with and without complications, to predict and prevent the development of autoimmune pathology.