Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc. This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non–cell-autonomous tumor suppressor gene for the Cdx2 gene in the gut.
OBJECTIVE Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.
Abstract Long noncoding RNAs (lncRNAs) are defined as RNA transcripts that are larger than 200 nt but do not appear to have protein-coding potential. Cumulative evidence points towards an important role of lncRNAs in cancer initiation, development, and progression. In this study we sought to evaluate the lncRNA expression profile of patients with cytogenetically normal acute myeloid leukemia (CN-AML). RNA sequencing of forty CN-AML patients allowed us to identify more than 8000 previously-undescribed lncRNAs. Using unsupervised analysis we observed a specific lncRNA signature dependent on the mutational status of the nucleophosmin (NPM1) gene. Sparse partial least squares discriminant analysis allowed us to identify a minimal set of 19 lncRNAs capable of discriminating NPM1-mutated from NPM1-wild type patients. Among these, we found that expression of the XLOC_087120 lncRNA inversely correlates with its neighboring histone-coding genes. XLOC_087120 also interacts with SUZ12, a component of the Polycomb Repressive Complex 2, suggesting a role for this lncRNA in the epigenetic repression of histone genes and therefore a potential impact on chromatin remodeling. Indeed, its overexpression in cell lines leads to a downregulation of histone genes. Furthermore, we demonstrated that mutant NPM1 modulates the nuclear/cytoplasmic localization of XLOC_087120. Altogether, these data suggest that lncRNAs should be considered as key players in the pathogenesis of acute myeloid leukemias. Citation Format: Etienne De Clara, Hanjing Ma, François Vergez, Cathy Quelen, Sébastien Dejean, Cécile Demur, Eric Delabesse, Christian Recher, Christian Touriol, Maria Paola Martelli, Brunangelo Falini, Pierre Brousset, Marina Bousquet. Long noncoding RNA expression in cytogenetically normal acute myeloid leukemia identifies a distinct signature associated with NPM1 mutations. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A27.
Olive latent virus 1 (OLV-1) belongs to the Necrovirus genus, Tombusviridae family and is pathogenic to olive, citrus and tulip plants. It is easily mechanically transmissible to indicator plants causing necrotic lesions and can be transmitted through the soil into the plant roots in the absence of biological vectors. Infected cells contain virus aggregates, inclusions made up of excess of viral coded peptides and extensive vesiculation in the cytoplasm. The virions are isometric with ca. 30 nm, possess a monopartite single-stranded positive-sense RNA genome sized 3700 nt with 5 open reading frames (ORFs) and small inter cistronic regions. ORF 1 encodes a polypeptide with a molecular weight of 23 kDa and the read through of its amber stop codon results in ORF 1 RT that encodes the virus RNA dependent RNA polymerase with 82 kDa. ORF2 and ORF3 encode two small peptides, with 8 kDa and 6 kDa, respectively, which appear to be involved in the virus cell-to-cell movement. ORF 4 is located in the 3′-terminal and encodes a protein with 30 kDa identified as the viral coat protein. The complete genomic sequences of two well characterized OLV-1 isolates (obtained from citrus and olive) are similar, revealing an overall nucleotide sequence identity of 95%. The electrophoretic profile of the dsRNAs recovered from infected tissues exhibits three major species with ca. 3.7, 1.5, and 1.3 kbp. Application of molecular techniques based on PCR and on dot blot hybridization has been successfully used for routine diagnosis of OLV-1 infections.
Les longs ARN non codants (lncRNAs) sont definis comme des transcrits de plus de 200nt et n'ayant pas de potentiel codant. Des etudes recentes ont demontre que les lncRNAs pouvaient etre impliques dans la regulation de la transcription, de la traduction, de la differenciation cellulaire, de l'expression genique, du cycle cellulaire et des modifications de la chromatine. De plus, il a ete montre un impact fonctionnel de certains lncRNAs dans le processus de cancerogenese mais nos connaissances actuelles sur ces molecules dans le cancer, et plus particulierement dans la leucemie, restent extremement limitees. Au cours de cette etude, nous avons analyse l'expression des lncRNAs par RNA-sequencing sur 40 patients atteints de leucemie aigue myeloblastique (LAM) a caryotype normal. Parmi les 11065 lncRNAs exprimes dans nos echantillons, nous avons identifie une signature de lncRNAs associee a la mutation de NPM1. Afin de mettre en evidence les fonctions putatives des lncRNAs selectionnes, nous avons utilise un algorithme de prediction d'interaction proteine/ARN. De maniere interessante, plus de la moitie des lncRNAs presentent des sites d'interactions potentiels a SUZ12, une sous unite du complexe PRC2 (Polycomb repressive complex 2), connu pour etre recrute par des lncRNAs pour la regulation epigenetique de genes cibles. Par RNA immunoprecipitation (RIP) de SUZ12, nous avons pu demontrer que le lncRNA XLOC_087120 interagissait avec SUZ12. De plus, son expression est anti-correlee avec celle des genes voisins codants des histones, suggerant un role dans la regulation negative des histones par ce lncRNA. L'impact de la deregulation de XLOC_087120 sur les histones a ete confirme par des experiences de surexpression et d'inhibition de ce lncRNA dans des lignees de LAM. De plus, meme si la mutation NPM1 ne semble pas affecter directement l'expression de ce lncRNA, des experiences d'infection de la forme mutee de NPM1 dans une lignee LAM ont montre que NPM1 pourrait reguler la localisation nucleaire/cytoplasmique de XLOC_087120 et moduler sa fonction de represseur. En conclusion, ces donnees suggerent que les lncRNAs sont des facteurs cles dans la pathogenese des LAMs.
Long non-coding RNAs are defined as transcripts larger than 200 nucleotides but without protein-coding potential. There is growing evidence of the important role of long non-coding RNAs in cancer initiation, development and progression. In this study, we sought to evaluate the long non-coding RNA expression profile of patients with cytogenetically normal acute myeloid leukemia (AML). RNA-sequencing of 40 cytogenetically normal AML patients allowed us to quantify 11,036 long non-coding RNAs. Among these, more than 8000 were previously undescribed long non-coding RNAs. Using unsupervised analysis, we observed a specific long non-coding RNA expression profile dependent on the mutational status of the NPM1 gene. Statistical analysis allowed us to identify a minimal set of 12 long non-coding RNAs capable of discriminating NPM1-mutated from NPM1-wild-type patients. These results were validated by qRT-PCR on an independent cohort composed of 134 cytogenetically normal AML patients. Furthermore, we have identified one putative biomarker, the long non-coding RNA XLOC_109948 whose expression pattern predicts clinical outcome. Interestingly, low XLOC_109948 expression indicates a good prognosis especially for NPM1-mutated patients. Transient transfection of GapmeR against XLOC_109948 in NPM1-mutated OCI-AML3 cell line treated with Ara-C or ATRA enhances apoptosis suggesting XLOC_109948 plays a role in drug sensitivity. This study improves our knowledge of the long non-coding RNA transcriptome in cytogenetically normal AML patients. We observed a distinct long non-coding RNA expression profile in patients with the NPM1 mutation. The newly identified XLOC_109948 long non-coding RNA emerged as a strong prognostic factor able to better stratify NPM1-mutated patients.
