Algorithms and Software for the Analysis of Large Complex Networks

The work presented intersects three main areas, namely graph algorithmics, network science and applied software engineering. Each computational method discussed relates to one of the main tasks of data analysis: to extract structural features from network data, such as methods for community detection; or to transform network data, such as methods to sparsify a network and reduce its size while keeping essential properties; or to realistically model networks through generative models

B CELL-SPECIFIC CONDITIONAL EXPRESSION OF MYD88P.L252P LEADS TO THE DEVELOPMENT OF DIFFUSE LARGE B CELL LYMPHOMA IN MICE

The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model, in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P)(the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL

Guidelines for the use of flow cytometry and cell sorting in immunological studies

International audienceThe classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127(-) and CD127(+) early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127(-) and CD127(+) ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127(-) ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127(+) ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis