Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une délétion du gène Tet2 et la mutation V617F du gène Jak2 favorisent la progression d'une néoplasie myéloproliférative et la transformation leucémique

Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms

Chen, Edwin ; Schneider, Rebekka K. ; Breyfogle, Lawrence J. ; Rosen, Emily A. ; Poveromo, Luke ; Elf, Shannon ; Ko, Amy ; Brumme, Kristina ; Levine, Ross ; Ebert, Benjamin L. ; Mullally, Ann

Signaling mutations (e.g. JAK2V617F) and mutations in genes involved in epigenetic regulation (e.g. TET2) are the most common co-occurring classes of mutations in myeloproliferative neoplasms (MPN). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPN such as myelofibrosis and leukemic transformation, suggesting that they may co-operate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F [...]

Menée à partir d'érythroblastes prélevés sur des patients atteints d'une néoplasie myéloproliférative, cette étude met en évidence différents mécanismes par lesquels, selon le sous-type de la maladie (polycythémie vraie ou thrombocytémie essentielle), la mutation V617F du gène JAK2 favorise la tumorigenèse

JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response

Chen, Edwin ; Ahn, Jong Sook ; Massie, Charlie E. ; Clynes, David ; Godfrey, Anna L. ; Li, Juan ; Park, Hyun Jung ; Nangalia, Jyoti ; Silber, Yvonne ; Mullally, Ann ; Gibbons, Richard J. ; Green, Anthony R.

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, via la régulation de l'expression de la protéine DEK, des mutations du gène SPOP favorisent le développement d'une tumeur de la prostate

Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Theurillat, Jean-Philippe P. ; Udeshi, Namrata D. ; Errington, Wesley J. ; Svinkina, Tanya ; Baca, Sylvan C. ; Pop, Marius ; Wild, Peter J. ; Blattner, Mirjam ; Groner, Anna C. ; Rubin, Mark A. ; Moch, Holger ; Privé, Gilbert G. ; Carr, Steven A. ; Garraway, Levi A.

Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer–associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en inhibant la voie de signalisation PI3K/AKT, le micro-ARN miR-105 exerce une fonction de suppresseur de tumeurs dans le carcinome hépatocellulaire

MicroRNA-105 suppresses cell proliferation and inhibits PI3K/AKT signaling in human hepatocellular carcinoma

Shen, Gang ; Rong, xiaoxiang ; Zhao, Jianbo ; Yang, Xuewei ; Li, Haibo ; Jiang, Hua ; Zhou, Qiang ; Ji, Tianxing ; Huang, Sicong ; Zhang, Jing ; Jia, Hongyun

A growing amount of evidence supports that microRNA (miRNA) dysregulation is involved in cancer progression by directly downregulating multiple targets. Elucidating the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In the current study, we found that miR-105 expression was markedly downregulated in both hepatocellular carcinoma (HCC) cell lines and clinical HCC tissues, compared to normal human hepatocyte and adjacent [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels un facteur de transcription, IRF5, favorise le développement d'un lymphome hodgkinien classique

Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma

Kreher, Stephan ; Bouhlel, M. Amine ; Cauchy, Pierre ; Lamprecht, Björn ; Li, Shuang ; Grau, Michael ; Hummel, Franziska ; Köchert, Karl ; Anagnostopoulos, Ioannis ; Jöhrens, Korinna ; Hummel, Michael ; Hiscott, John ; Wenzel, Sören-Sebastian ; Lenz, Peter ; Schneider, Markus ; Küppers, Ralf ; Scheidereit, Claus ; Giefing, Maciej ; Siebert, Reiner ; Rajewsky, Klaus ; Lenz, Georg ; Cockerill, Peter N. ; Janz, Martin ; Dörken, Bernd ; Bonifer, Constanze ; Mathas, Stephan

Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a [...]

Cet article passe en revue les travaux récents sur le rôle joué par des isoformes tronquées de la protéine p53 dans la transition épithélio-mésenchymateuse et la progression tumorale

Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression

Engelmann, David ; Pützer, Brigitte M.

The prevailing view has been that N-terminally truncated p53 family isoforms (

Cette étude présente un modèle qui, basé sur les concepts de dynamique des populations, intègre les avantages évolutifs des mutations "conductrices" et les coûts évolutifs des mutations "passagères" pour rendre compte de la progression d'une tumeur

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland, Christopher D. ; Mirny, Leonid A. ; Korolev, Kirill S.

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations—a natural consequence of cancer’s elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely [...]