E-Biothon : Une plate-forme pour accélérer les recherches en biologie, santé et environnement

National audienceE-Biothon : Une plate-forme pour accélérer les recherches en biologie, santé et environnemen

High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia

In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML

E-Biothon : Une plate-forme pour accélérer les recherches en biologie, santé et environnement

National audienceE-Biothon : Une plate-forme pour accélérer les recherches en biologie, santé et environnemen

Pre-exascale Architectures: OpenPOWER Performance and Usability Assessment for French Scientific Community

International audienceExascale implies a major pre-requisite in terms of energy efficiency, as an improvement of an order of magnitude must be reached in order to stay within an acceptable envelope of 20 MW. To address this objective and to continue to sustain performance, HPC architectures have to become denser, embedding many-core processors (to several hundreds of computing cores) and/or become heterogeneous, that is, using graphic processors or FPGAs. These energy-saving constraints will also affect the underlying hardware architectures (e.g., memory and storage hierarchies, networks) as well as system software (runtime, resource managers, file systems, etc.) and programming models. While some of these architectures, such as hybrid machines, have existed for a number of years and occupy noticeable ranks in the TOP 500 list, they are still limited to a small number of scientific domains and, moreover, require significant porting effort. However, recent developments of new paradigms (especially around OpenMP and OpenACC) make these architectures much more accessible to programmers. In order to make the most of these breakthrough upcoming technologies, GENCI and its partners have set up a technology watch group and lead collaborations with vendors, relying on HPC experts and early adopted HPC solutions. The two main objectives are providing guidance and prepare the scientific communities to challenges of exascale architectures

MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

Abstract In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL–AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease. Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478–97. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371</jats:p