Menée sur 5 cas d'une forme hyperploïde (51-67 chromosomes) de leucémie aiguë lymphoblastique et une lignée cellulaire dérivée d'un clone presque haploïde (23-29 chromosomes), cette étude évalue l'intérêt d'un séquençage de nouvelle génération pour la stratification du risque dans les leucémies lymphoblastiques de forme presque haploïde

Next-generation-sequencing-based risk stratification and identification of new genes involved in structural and sequence variations in near haploid lymphoblastic leukemia

Chen, Cai ; Bartenhagen, Christoph ; Gombert, Michael ; Okpanyi, Vera ; Binder, Vera ; Röttgers, Silja ; Bradtke, Jutta ; Teigler-Schlegel, Andrea ; Harbott, Jochen ; Ginzel, Sebastian ; Thiele, Ralf ; Fischer, Ute ; Dugas, Martin ; Hu, Jianda ; Borkhardt, Arndt

Near haploidy (23–29 chromosomes) is a numerical cytogenetic aberration in childhood acute lymphoblastic leukemia (ALL) associated with particularly poor outcome. In contrast, high hyperdiploidy (51–67 chromosomes) has a favorable prognosis. Correct classification and appropriate risk stratification of near haploidy is frequently hampered by the presence of apparently high hyperdiploid clones that arise by endoreduplication of the original near haploid clone. We evaluated [...]

Menée sur des paires d'échantillons de tissu tumoral et de tissu normal prélevés sur 149 patients atteints d'un adénocarcinome de l'œsophage, cette étude identifie 26 gènes affectés par des mutations fréquentes

Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Dulak, Austin M. ; Stojanov, Petar ; Peng, Shouyong ; Lawrence, Michael S. ; Fox, Cameron ; Stewart, Chip ; Bandla, Santhoshi ; Imamura, Yu ; Schumacher, Steven E. ; Shefler, Erica ; McKenna, Aaron ; Carter, Scott L. ; Cibulskis, Kristian ; Sivachenko, Andrey ; Saksena, Gordon ; Voet, Douglas ; Ramos, Alex H. ; Auclair, Daniel ; Thompson, Kristin ; Sougnez, Carrie ; Onofrio, Robert C. ; Guiducci, Candace ; Beroukhim, Rameen ; Zhou, Zhongren ; Lin, Lin ; Lin, Jules ; Reddy, Rishindra ; Chang, Andrew ; Landrenau, Rodney ; Pennathur, Arjun ; Ogino, Shuji ; Luketich, James D. ; Golub, Todd R. ; Gabriel, Stacey B. ; Lander, Eric S. ; Beer, David G. ; Godfrey, Tony E. ; Getz, Gad ; Bass, Adam J.

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ~15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data [...]

Cet article passe en revue les travaux récents sur des mécanismes impliquant des composants du métabolisme oncogénique dans la formation de cellules souches cancéreuses et la tumorigenèse

Unraveling the mystery of cancer metabolism in the genesis of tumor-initiating cells and development of cancer

Zhang, Gaochuan ; Yang, Ping ; Guo, Pengda ; Miele, Lucio ; Sarkar, Fazlul H. ; Wang, Zhiwei ; Zhou, Quansheng

Robust anaerobic metabolism plays a causative role in the origin of cancer cells; however, the oncogenic metabolic genes, factors, pathways, and networks in genesis of tumor-initiating cells (TICs) have not yet been systematically surmirized. In addition, the mechanisms of oncogenic metabolism in the genesis of TICs are enigmatic. In this review, we discussed multiple cancer metabolism-related genes (MRGs) that are overexpressed in TICs and are responsible for inducing pluripotent stem cells. [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en régulant les voies de signalisation oncogénique Akt et c-myc, la protéine kinase Hunk favorise le développement d'un cancer du sein induit par la perte du gène Pten

Hunk negatively regulates c-myc to promote Akt-mediated cell survival and mammary tumorigenesis induced by loss of Pten

Yeh, Elizabeth S. ; Belka, George K. ; Vernon, Ann E. ; Chen, Chien-Chung ; Jung, Jason J. ; Chodosh, Lewis A.

The protooncogenes Akt and c-myc each positively regulate cell growth and proliferation, but have opposing effects on cell survival. These oncogenes cooperate to promote tumorigenesis, in part because the prosurvival effects of Akt offset the proapoptotic effects of c-myc. Akt’s ability to counterbalance c-myc’s proapoptotic effects has primarily been attributed to Akt-induced stimulation of prosurvival pathways that indirectly antagonize the effects of c-myc. We report a more direct mechanism [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le micro-ARN 9 dans la formation des cellules myéloïdes et le développement d'une leucémie induite par une surexpression du gène EVI1

Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis

Senyuk, Vitalyi ; Zhang, Yunyuan ; Liu, Yang ; Ming, Ming ; Premanand, Kavitha ; Zhou, Lan ; Chen, Ping ; Chen, Jianjun ; Rowley, Janet D. ; Nucifora, Giuseppina ; Qian, Zhijian

MicroRNA-9 (miR-9) is emerging as a critical regulator of organ development and neurogenesis. It is also deregulated in several types of solid tumors; however, its role in hematopoiesis and leukemogenesis is not yet known. Here we show that miR-9 is detected in hematopoietic stem cells and hematopoietic progenitor cells, and that its expression increases during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis and promotes apoptosis in vitro [...]

Menée in vitro, à l'aide de xénogreffes et sur 127 échantillons tumoraux prélevés sur des patients chinois atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel une acétylation de la lysine 5 régule l'expression de la lactate déshydrogénase A dans les tumeurs

Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer

Zhao, Di ; Zou, Shao-Wu ; Liu, Ying ; Zhou, Xin ; Mo, Yan ; Wang, Ping ; Xu, Yan-Hui ; Dong, Bo ; Xiong, Yue ; Lei, Qun-Ying ; Guan, Kun-Liang

Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1± may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'activité transcriptionnelle du récepteur des androgènes, l'ubiquitine-ligase Siah2 favorise le développement d'un cancer de la prostate résistant à la castration

The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity

Qi, Jianfei ; Tripathi, Manisha ; Mishra, Rajeev ; Sahgal, Natasha ; Fazil, Ladan ; Ettinger, Susan ; Placzek, William J ; Claps, Giuseppina ; Chung, Leland W K. ; Bowtell, David ; Gleave, Martin ; Bhowmick, Neil ; Ronai, Ze ev A

Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel une surexpression du récepteur à activité tyrosine kinase MET et la perte du gène TP53 favorisent le développement d'un sous-type de cancer du sein triplement négatif

Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer

Knight, Jennifer F. ; Lesurf, Robert ; Zhao, Hong ; Pinnaduwage, Dushanthi ; Davis, Ryan R. ; Saleh, Sadiq M. I. ; Zuo, Dongmei ; Naujokas, Monica A. ; Chughtai, Naila ; Herschkowitz, Jason I. ; Prat, Aleix ; Mulligan, Anna Marie ; Muller, William J. ; Cardiff, Robert D. ; Gregg, Jeff P. ; Andrulis, Irene L. ; Hallett, Michael T. ; Park, Morag

Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Metmt) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Metmt mice with conditional loss of murine p53 [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle essentiel joué par une ubiquitine-ligase, Fbw7, dans la régulation des cellules souches de leucémie myéloïde chronique

Regulation of c-Myc Ubiquitination Controls Chronic Myelogenous Leukemia Initiation and Progression

Reavie, Linsey ; Buckley, Shannon M ; Loizou, Evangelia ; Takeishi, Shoichiro ; Aranda-Orgilles, Beatriz ; Ndiaye-Lobry, Delphine ; Abdel-Wahab, Omar ; Ibrahim, Sherif ; Nakayama, Keiichi I ; Aifantis, Iannis

The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or [...]

Menée sur des lignées cellulaires de cancer du pancréas, cette étude met en évidence le rôle joué par les cellules stellaires pancréatiques et la protéine STAT3 dans l'échappement au système immunitaire

Pancreatic cancer associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner

Mace, Thomas A ; Ameen, Zeenath ; Collins, Amy ; Wojcik, Sylwia E. ; Mair, Markus ; Young, Gregory S. ; Fuchs, James R ; Eubank, Tim D ; Frankel, Wendy L ; Bekaii-Saab, Tanios ; Bloomston, Mark ; Lesinski, Gregory B.

Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide pro-survival signals to tumors, however little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n=7) were generated from human [...]