Menée sur plusieurs cohortes de patients atteints d'un syndrome myélodysplasique, cette étude met en évidence le rôle joué par des mutations du gène BCOR dans la progression de la maladie vers une leucémie myéloïde aiguë

BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders

Damm, Frederik ; Chesnais, Virginie ; Nagata, Yasunobu ; Yoshida, Kenichi ; Scourzic, Laurianne ; Okuno, Yusuke ; Itzykson, Raphaël ; Sanada, Masashi ; Shiraishi, Yuichi ; Gelsi-Boyer, Véronique ; Renneville, Aline ; Miyano, Satoru ; Mori, Hiraku ; Shih, Lee-Yung ; Park, Sophie ; Dreyfus, François ; Guerci-Bresler, Agnes ; Solary, Eric ; Rose, Christian ; Cheze, Stéphane ; Prebet, Thomas ; Vey, Norbert ; Legentil, Marion ; Duffourd, Yannis ; de Botton, Stéphane ; Preudhomme, Claude ; Birnbaum, Daniel ; Bernard, Olivier A. ; Ogawa, Seishi ; Fontenay, Michaela ; Kosmider, Olivier

Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to AML remain a challenge in disease management. Using whole-exome-sequencing of a MDS patient, we identified a somatic mutation in BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified a total of 15 patients with inactivating BCOR mutations (15/354=4.2%) and 3 with BCORL1 mutations (3/354=0.8%). BCOR mutations were associated with RUNX1 (P=0.002) and [...]

Menée sur une cohorte de 366 patients atteints d'un lymphome folliculaire, puis sur 33 patients dont la maladie a évolué en lymphome folliculaire transformé, cette étude met en évidence de fréquentes mutations du gène EZH2

EZH2 mutations are frequent and represent an early event in follicular lymphoma

Bödör, Csaba ; Grossmann, Vera ; Popov, Nikolay ; Okosun, Jessica ; O'Riain, Ciarán ; Tan, King ; Marzec, Jacek ; Araf, Shamzah ; Wang, Jun ; Lee, Abigail M. ; Clear, Andrew ; Montoto, Silvia ; Matthews, Janet ; Iqbal, Sameena ; Rajnai, Hajnalka ; Rosenwald, Andreas ; Ott, German ; Campo, Elias ; Rimsza, Lisa M. ; Smeland, Erlend B. ; Chan, Wing C. ; Braziel, Rita M. ; Staudt, Louis M. ; Wright, George ; Lister, T. Andrew ; Elemento, Olivier ; Hills, Robert ; Gribben, John ; Chelala, Claude ; Matolcsy, András ; Kohlmann, Alexander ; Haferlach, Torsten ; Gascoyne, Randy D. ; Fitzgibbon, Jude

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=366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n=33). Mutations were detected at 3 recurrent mutation hot-spots (Y646, A682 and A692) in 27% of FL cases [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le gène suppresseur de tumeurs p16INK4a exerce une fonction protectrice dans les cellules en prolifération présentant un dysfonctionnement des télomères

p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses

Wang, Yang ; Sharpless, Norman ; Chang, Sandy

Dysfunctional telomeres limit cellular proliferative capacity by activating the p53-p21– and p16INK4a-Rb–dependent DNA damage responses (DDRs). The p16INK4a tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo. While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16INK4a in response to telomere dysfunction remains unclear. Here, we [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la signalisation NF-

Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-

Kuo, Hsu-Ping ; Wang, Zhong ; Lee, Dung-Fang ; Iwasaki, Masayuki ; Duque-Afonso, Jesus ; Wong, Stephen H K. ; Lin, Chiou-Hong ; Figueroa, Maria E ; Su, Jie ; Lemischka, Ihor R ; Cleary, Michael L

MLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations; however, the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par la protéine RUNX1 dans le développement d'une leucémie myéloïde aiguë associée aux anomalies chromosomiques t(8:21) et inv(16)

Addiction of t(8;21) and inv(16) Acute Myeloid Leukemia to Native RUNX1

Ben-Ami, Oren ; Friedman, Dan ; Leshkowitz, Dena ; Goldenberg, Dalia ; Orlovsky, Kira ; Pencovich, Niv ; Lotem, Joseph ; Tanay, Amos ; Groner, Yoram

The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBF

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le gène LMX1B favorise le développement et la progression d'un cancer de l'ovaire

Identification of LMX1B as a novel oncogene in human ovarian cancer

He, L. ; Guo, L. ; Vathipadiekal, V. ; Sergent, P. A. ; Growdon, W. B. ; Engler, D. A. ; Rueda, B. R. ; Birrer, M. J. ; Orsulic, S. ; Mohapatra, G.

Ovarian cancers are thought to result from the accumulation of multiple genetic aberrations that transform ovarian and/or fallopian tube surface epithelial cells, allowing for their abnormal growth, proliferation and metastasis. In the report presented here, we carried out genome-wide copy-number analysis using comparative genomic hybridization on a panel of mouse ovarian cancer (OVCA) cell lines previously established in our laboratory. We identified a recurrent focal amplification on mouse [...]

Cet article passe en revue les travaux récents sur les mécanismes de nature évolutionniste à l'œuvre dans les cellules cancéreuses qui se disséminent dans le corps humain à partir des tumeurs primitives

Selection and adaptation during metastatic cancer progression

Klein, Christoph A.

Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells [...]

Cet article passe en revue les travaux récents sur le rôle du récepteur des cellules B dans le développement et la progression des lymphomes

B-cell receptor signaling as a driver of lymphoma development and evolution

Niemann, Carsten U. ; Wiestner, Adrian

The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme de coopération entre les gènes HER2 et MYC favorisant le comportement agressif d'un cancer du sein

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer

Nair, R. ; Roden, D. L. ; Teo, W. S. ; McFarland, A. ; Junankar, S. ; Ye, S. ; Nguyen, A. ; Yang, J. ; Nikolic, I. ; Hui, M. ; Morey, A. ; Shah, J. ; Pfefferle, A. D. ; Usary, J. ; Selinger, C. ; Baker, L. A. ; Armstrong, N. ; Cowley, M. J. ; Naylor, M. J. ; Ormandy, C. J. ; Lakhani, S. R. ; Herschkowitz, J. I. ; Perou, C. M. ; Kaplan, W. ; O'Toole, S. A. ; Swarbrick, A.

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un carcinome du rhinopharynx, puis sur des lignées cellulaires, cette étude met en évidence le rôle joué par une surexpression de la protéine SATB1, en association avec une protéine membranaire du virus d'Epstein-Barr (LMP-1), dans la progression de la maladie

Over-expression of the special AT rich sequence binding protein 1 (SATB1) promotes the progression of nasopharyngeal carcinoma: association with EBV LMP-1 expression

Shen, Zhihua ; Zeng, Yumei ; Guo, Junli ; Wu, Yanxia ; Jiang, Xiaofan ; Ding, Ranran ; Wu, Changli ; Li, Rujia ; Luo, Botao ; Zeng, Chao ; Jiang, Hanguo ; Jie, Wei

BACKGROUND:Special AT rich sequence binding protein 1 (SATB1) plays a crucial role in the biology of various types of human cancer. However, the role of SATB1 in human nasopharyngeal carcinoma (NPC) remains unknown. In the present study, we sought to investigate the contribution of aberrant SATB1 expression in the progression of NPC and its association with the Epstein Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1). METHODS:Immunohistochemical analysis was performed to detect SATB1 [...]

Menée sur des cellules de leucémie, cette étude évalue la faisabilité d'une méthode d'analyse des anomalies génomiques à l'échelle d'une seule cellule

Single cell mutational profiling and clonal phylogeny in cancer

Potter, Nicola E ; Ermini, Luca ; Papaemmanuil, Elli ; Cazzaniga, Giovanni ; Vijayaraghavan, Gowri ; Titley, Ian ; Ford, Anthony ; Campbell, Peter ; Kearney, Lyndal ; Greaves, Mel

The development of cancer is a dynamic evolutionary process in which intra-clonal, genetic diversity provides a substrate for clonal selection and a source of therapeutic escape. The complexity and topography of intra-clonal genetic architecture has major implications for biopsy-based prognosis and for targeted therapy. High depth, next generation sequencing (NGS) efficiently captures the mutational load of individual tumours or biopsies. But, being a snapshot portrait of total DNA, it [...]