Cette étude met en évidence le rôle joué par des mutations du type "duplication interne en tandem" du gène FLT3 dans le développement d'une leucémie myéloïde aiguë et la résistance au quizartinib

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia

Smith, Catherine C. ; Wang, Qi ; Chin, Chen-Shan ; Salerno, Sara ; Damon, Lauren E. ; Levis, Mark J. ; Perl, Alexander E. ; Travers, Kevin J. ; Wang, Susana ; Hunt, Jeremy P. ; Zarrinkar, Patrick P. ; Schadt, Eric E. ; Kasarskis, Andrew ; Kuriyan, John ; Shah, Neil P.

Effective targeted cancer therapeutic development depends upon distinguishing disease-associated ‘driver’ mutations, which have causative roles in malignancy pathogenesis, from ‘passenger’ mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations [...]

Menée sur deux cohortes successives de 96 et 157 cas de lymphome diffus à grandes cellules B, cette étude identifie une nouvelle fusion de gènes (TBL1XR1 et TP63) associée à un sous-type de la maladie

TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma

Scott, David W ; Mungall, Karen L ; Ben-Neriah, Susana ; Rogic, Sanja ; Morin, Ryan D ; Slack, Graham W ; Tan, King L ; Chan, Fong Chun ; Lim, Raymond S ; Connors, Joseph M ; Marra, Marco A ; Mungall, Andrew J ; Steidl, Christian ; Gascoyne, Randy D

Recently the landscape of single base mutations in diffuse large B cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal centre B cell-like (GCB) DLBCL is 5% (6/115). The fusion appears exclusive to GCB, and was not seen in [...]

Cet article passe en revue les travaux récents sur les anomalies génétiques associées au développement et à la progression d'un myélome multiple

The genetic architecture of multiple myeloma

Morgan, Gareth J. ; Walker, Brian A. ; Davies, Faith E.

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, [...]

Menée sur des lignées cellulaires de cancer du côlon, cette étude identifie des modifications reproductibles de l'épigénome, relatives à des éléments amplificateurs de l'expression de certains gènes, favorisant la cancérogenèse

Epigenomic Enhancer Profiling Defines a Signature of Colon Cancer

Akhtar-Zaidi, Batool ; Cowper-Sal·lari, Richard ; Corradin, Olivia ; Saiakhova, Alina ; Bartels, Cynthia F. ; Balasubramanian, Dheepa ; Myeroff, Lois ; Lutterbaugh, James ; Jarrar, Awad ; Kalady, Matthew F. ; Willis, Joseph ; Moore, Jason H. ; Tesar, Paul J. ; Laframboise, Thomas ; Markowitz, Sanford ; Lupien, Mathieu ; Scacheri, Peter C.

Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, despite the fact that distal regulatory elements play a central role in controlling transcription patterns. Here, we utilize the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly [...]

Menée à l'échelle de cellules individuelles sur 53 tumeurs de cancer du sein associées à des mutations du gène BRCA1, cette étude analyse l'ordre temporel des anomalies somatiques concernant les gènes BRCA1, PTEN et p53

Evolutionary pathways in BRCA1-associated breast tumors

Martins, Filipe C. ; De, Subhajyoti ; Almendro, Vanessa ; Gonen, Mithat ; Park, So Yeon ; Blum, Joanne L. ; Herlihy, William ; Ethington, Gabrielle ; Schnitt, Stuart J. ; Tung, Nadine ; Garber, Judy E. ; Fetten, Katharina ; Michor, Franziska ; Polyak, Kornelia

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events based on the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with [...]

Cet article passe en revue les travaux récents sur le rôle de la voie de signalisation mTOR dans les maladies humaines, dont le cancer, et le vieillissement

mTOR Signaling in Growth Control and Disease

Laplante, Mathieu ; Sabatini, David M

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss [...]

Cette étude met en évidence un mécanisme par lequel la voie de signalisation de la bêta-caténine est susceptible d'induire la formation d'un astrocytome

β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas

Yang, Chunzhang ; Iyer, Rajiv R. ; Yu, Albert C. H. ; Yong, Raymund L. ; Park, Deric M. ; Weil, Robert J. ; Ikejiri, Barbara ; Brady, Roscoe O. ; Lonser, Russell R. ; Zhuang, Zhengping

Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We [...]

Cet article passe en revue les travaux récents sur le rôle de la signalisation des cellules souches du mésenchyme dans la progression d'un cancer

Mesenchymal stem cell signaling in cancer progression

Torsvik, Anja ; Bjerkvig, Rolf

Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular [...]

Menée sur des lignées cellulaires de cancers de la prostate et du sein ainsi que sur des échantillons tumoraux, cette étude met en évidence un mécanisme par lequel le gène EZH2 favorise l'invasion des cellules cancéreuses

Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer

Ren, Gang ; Baritaki, Stavroula ; Marathe, Himangi ; Feng, Jingwei ; Park, Sungdae ; Beach, Sandy ; Bazeley, Peter S. ; Beshir, Anwar B ; Fenteany, Gabriel ; Mehra, Rohit ; Daignault, Stephanie ; Al Mulla, Fahd ; Keller, Evan ; Bonavida, Ben ; de la Serna, Ivana ; Yeung, Kam C

Epigenetic modifications such as histone methylation play an important role in human cancer metastasis. EZH2, which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor RKIP have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical [...]

Menée sur des mouches, cette étude montre qu'un mécanisme de délaminage cellulaire permet de maintenir un épithélium à l'équilibre et suggère que sa dérégulation est liée au processus invasif du cancer

Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding

Marinari, Eliana ; Mehonic, Aida ; Curran, Scott ; Gale, Jonathan ; Duke, Thomas ; Baum, Buzz

The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing. In crowded regions of the [...]

Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein et à l'aide de xénogreffes, cette étude suggère que la surexpression d'un produit du gène BRCA1, BRCA1-IRIS, est associée au caractère agressif des tumeurs, en particulier chez les patientes atteintes d'un cancer du sein HER2+ ou basal-like triplement négatif

BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

Shimizu, Yoshiko ; Luk, Hugh ; Horio, David ; Miron, Penelope ; Griswold, Michael ; Iglehart, Dirk ; Hernandez, Brenda ; Killeen, Jeffrey ; ElShamy, Wael M.

Introduction:Women with HER2+ or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for [...]

Cet article passe en revue les travaux récents sur le processus métastatique dans le cancer du sein

New insights into the mechanisms of organ-specific breast cancer metastasis

Lorusso, Girieca ; Rüegg, Curzio

Despite the substantial advances obtained in the treatment of localized malignancies, metastatic disease still lacks effective treatment and remains the primary cause of cancer mortality, including in breast cancer. Thus, in order to improve the survival of cancer patients it is necessary to effectively improve prevention or treatment of metastasis. To achieve this goal, complementary strategies can be envisaged: the first one is the eradication of established metastases by adding novel [...]