Genetic and Epigenetic control of normal and malignant hematopoiesis
Institut de Recherche Saint Louis / INSERM U944 / CNRS UMR7212
contact : Antonio Maraver (IRCM-Inserm)
Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow. It is characterized by the overproduction of immature white blood cells, called myeloblasts, which can crowd out healthy blood cells and lead to a variety of symptoms, including fatigue, infection, and bleeding. AML is the most common acute leukemia diagnosed in adult and has a high relapse rate with a dismal overall 5-year survival of 24%. AML is a complex disease that is driven by a variety of genetic and epigenetic changes but its exact causes are still not fully understood.
Enhancers are non-coding regions of DNA that play a crucial role in regulating gene expression. They act as binding sites for transcription factors to promote gene transcription. Super-enhancers are clusters of enhancers that are characterized by a high density of transcription factor binding sites. They have been characterized as a particular class of enhancers controlling cell type specific gene expression programs and tend to be enriched around and control oncogenes. In leukemia, enhancers have been shown to be key players in the development and progression of the disease. Identification of the direct functional and physical relationship between Super-Enhancers and their target oncogenes could help decipher complex coordinated gene expression programs that lead to leukemogenesis. Study of the dynamic interplay between enhancers, and gene expression program could unravel novel collaborative oncogenic mechanisms and help design more effective combinatorial therapies.
In a recent study we hypothesized that important regulatory regions such as Super-Enhancers could control simultaneously expression of genes cooperating in functional modules to promote leukemia development. To identify key Super-Enhancers that are involved in AML cell growth and survival, we used a screening methodology called CRISPRi, which relies on the use of a deactivated Cas9 protein fused to a KRAB domain to target and inactivate Super-Enhancers. We deployed this strategy in the ETO2-GLIS2 fusion driven model of acute megakaryoblastic leukemia (AMKL), an aggressive pediatric myeloid leukemia with poor prognosis, which mainly relies on the ETO2-GLIS2 as the transforming lesion. Among the top hits of our screen, we identified a novel Super-Enhancer, located 5’ to the KIT gene on chromosome 4. We found that it directly interacts and regulates the expression of KIT and PDGFRA genes, which are both required for leukemia progression in vitro and in vivo. These results suggest that Super-Enhancers could control simultaneously the expression of genes cooperating in functional modules to promote leukemia development.
Our findings provide new insights into the molecular mechanisms underlying AML pathogenesis and highlight the importance of understanding the role of enhancers and Super-Enhancers in the development and progression of leukemias. We believe that systematic screening of essential Super-Enhancers can reveal coordinated regulation of genes involved in cancer cell transformation and cancer progression and could help to uncover novel therapeutic approaches.
Cancer Research Centre of Toulouse (CRCT)/Inserm/Université Paul Sabatier/CNRS
contact : Eric Julien (CNRS/Inserm)
En réponse aux thérapies anti-cancéreuses, des voies de signalisations peuvent être activées et induire une résistance des cellules cancéreuses à ces traitements. Ces voies sont généralement régulées par des oncoprotéines et des interactions protéine-protéine. Notre projet consiste à déterminer les mécanismes moléculaires contrôlant la résistance des tumeurs pancréatiques, en identifiant et inhibant des (onco)protéines et/ou des interactions protéine-protéine cibles. Pour cela, nous développons des méthodes et outils innovants basés sur la technologie des anticorps intracellulaires. Ces anticorps dérivent du domaine variable d’immunoglobulines à simple chaine lourde de camélidés et sont appelés « nanobody ». Ils se lient de façon spécifique à leur cible et peuvent ainsi bloquer leur(s) fonction(s) dans les cellules. Il est également possible de fonctionnaliser ces anticorps avec des molécules effectrices. Par exemple, les anticorps dégradeurs sont fusionnés à une E3 ubiquitine ligase pour induire la dégradation spécifique de leur cible. En utilisant ces technologies, nous inhibons à façon des médiateurs de voies de signalisation afin de définir l’implication de ces dernières dans la résistance des cellules cancéreuses pancréatiques
PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France.
Contact : Céline Gongora (inserm)
"The company develops (1) innovative tools for early detection of solid tumors, and (2) cutting-edge human-derived 3D models to support drug development and precision medicine.
It is well known that Drug-induced liver injury (DILI) is a major challenge in drug development and most of the compounds that passed preclinical testing fail clinical trials because of liver toxicity. One reason of this failure is that existing preclinical models are unable to reproduce the interindividual heterogeneity of drug response in a population. PredictCan Biotechnologies SAS releases GenuineSelect-TOX, a new donor-dependent reprogramming multicellular spheroid model that recapitulates interindividual heterogeneity found in a cohort of people. Hepatic toxicity analysis revealed that the model could accurately predict clinical DILI confirmed by the FDA (FDA DILIrank). Moreover, the model could also predict chemical-induced hepatotoxicity based on host-risk factors such as age and sex. GenuineSelect-TOX is the first preclinical model that offers the possibility to (1) perform Clinical Trials-in-a-Dish for DILI, and (2) challenge DILI based on host-risk factors. At PredictCan Biotechnologies SAS, we offer an innovative solution to generate on-demand cohorts of healthy individuals for fit-on-purpose analysis of hepatotoxicity of your molecules."
Fox Biosystems
contact: martine.pugniere@inserm.fr
En bref:
La technologie SPR (Surface Plasmon Resonance) a permis de grandes avancées dans le domaine des études d’interaction mais la nécessité d’utiliser des canaux microfluidiques pour acheminer les échantillons est une limitation majeure pour certaines applications. FOx Biosystems a développé une technologie SPR basée sur des fibres optiques qui plongent directement dans les échantillons afin d’y mesurer en temps réel la fixation de protéines et autres biomolécules à leurs partenaires. Cette mise en œuvre unique de la SPR rend plus simple les applications classiques de dosage et de cinétique, mais elle rend surtout possibles de nouvelles applications : mesures d’échantillons dans des matrices complexes comme le sang total, détection de gros objets comme les vésicules extracellulaires, les virus et les phages notamment pour accélérer le phage display. L'analyse s’effectue en barrettes ou microplaques de tubes PCR, traitant jusqu'à 96 échantillons par run. Le principe de la technologie SPR par fibre optique sera expliqué, et ses applications seront discutées lors de ce séminaire.
Pour toute question, Martine Pugnière (Martine.Pugniere@inserm.fr) ou Florian Bossard, Bossard.F@foxbiosystems.com.
University of Toronto, Ontario, Canada
Contact: jean-pierre.pouget@inserm.fr
Dr. Raymond Reilly is a professor and the Director of the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy, University of Toronto. His research is focused on the development, preclinical evaluation and advancement to first-in-humans clinical trials of novel radiopharmaceuticals for imaging and treatment of cancer. He has published more than 180 scientific papers in this field and has trained almost 40 graduate students in the radiopharmaceutical sciences. Professor Reilly’s research is supported by the Canadian Institutes of Health Research, the Canadian Cancer Society and the Natural Sciences and Engineering Research Council of Canada. He will be speaking on his recent work to develop radiation nanomedicines for local treatment of triple-negative breast cancer and glioblastoma multiforme, the most common and lethal form of brain cancer.
Centre d'Immunologie Marseille-Luminy and Inflammation Biology, King’s College London, UK
Contact: nathalie.bonnefoy@inserm.fr
CRCT, Toulouse
contact: marie-alix.poul@inserm.fr
CRCT, Toulouse
Contact: marie-alix.poul@inserm.fr
Situé dans le Parc Euromédecine, l'Institut de Recherche en Cancérologie de Montpellier (U1194) est localisé sur le Campus Val d'Aurelle (ICM, Institut régional du Cancer Montpellier / Val d'Aurelle).
Centre de Recherche U1194 soutenu par l'Inserm, l'Université de Montpellier et l'Institut du Cancer de Montpellier (ICM)
Institut de Recherche en Cancérologie de
