Lymphome non hodgkinien

Résumé

Les sont des néoplasies développées à partir des tissus lymphoïdes, qui ne sont pas des lymphomes de Hodgkin. Un lymphome est un cancer du système lymphatique aux dépens des lymphocytes. Le système lymphatique comprend la moelle osseuse, la rate, le thymus, les ganglions lymphatiques et les vaisseaux lymphatiques ; il assure la défense de l'organisme contre les microbes, parasites, toxines, corps étrangers Histoire Le lymphome de Hodgkin a fait l'objet d'un consensus rapide, laissant dans cette classe indéterminée les autres nombreux lymphomes, causant un nombre important de maladies différentes tant par leurs symptômes que par leur dangerosité. Henry Rappaport proposa une classification entre 1956 et 1966 qui fut la première largement acceptée. En 1982 apparu la Working Formulation qui fait usage du terme, encore largement en usage bien que rendue obsolete en 2008 par la classification des lymphomes de l'Organisation mondiale de la santé. LNH est une dénomination q

Source officielle

https://fr.wikipedia.org/wiki/Lymphome_non_hodgkinien

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Epigenetics plays an important role in cancer development and progression. Cancer cells hijack the epigenome by modifying the histone protein units responsible for packaging DNA, or by modifying the DNA itself, resulting in changes to chromatin topology and transcriptional programming within the cell. In this thesis, I report our investigation to uncover the mechanisms of epigenetic regulation and how epigenetic control of transcriptional programming goes awry in cancer. We investigate these processes in two separate contexts. In our first study, we investigate the mechanisms by which EZH2 oncogenic mutations alter structure and function of topologically associating domains in non-Hodgkin lymphoma. The process of chromatin folding leads to a systematic arrangement of hierarchical structural and regulatory elements found within the nucleus. A topologically associating domain (TAD) is a regulatory unit of self interacting DNA, where the transcription of the genes within a TAD is usually dictated by the presence of active (H3K36me3) or inactive (H3K27me3) histone marks. In cancer, the somatic point mutation in EZH2Y646X leads to a genome wide increase in H3K27me3, associated with transcriptional repression. While this alteration leads to changes in the global epigenetic status of the cell, its impact on chromatin organization and TAD-related function remain unclear. By combining transcriptomics and epigenetics with analyses of chromatin structure, we demonstrate a functional interplay between TADs and the epigenetic and transcriptional program of the genes found within them. This balance is altered by EZH2Y646X, leading to the synergistic silencing of entire domains directly targeting cell differentiation and tumor suppressive programs. A closer look reveals that the silencing of tumor suppressive TADs are coupled with structural modifications and changes in promoter interactions within EZH2Y646X target TAD6.139. Impressively, the TADâs transcriptional and epigenetic programs are restored by pharmacological inhibition of EZH2Y646X. Our results indicate that EZH2Y646X alters the topology and function of chromatin domains to promote synergistic oncogenic programs. In our second study, we dissect the epigenetic, transcriptomic, and metabolic signaling dependencies using a novel model of central nervous system primitive neural ectodermal tumors (CNS-PNETs). Central nervous system (CNS) tumors are the leading cause of cancer-associated death in children. Primitive neural-ectodermal tumors (CNS-PNETs) are a particularly aggressive subtype of embryonal CNS-tumor, with a five-year overall survival rate in less than 50% of patients. Despite sharing a similar cell of origin of other CNS tumors, CNS-PNETs have a different anatomical location, unique genetic and epigenetic features, and significantly worse clinical outcome. In addition, a lack of in vivo models for studying CNS tumors challenges the opportunity to dissect the genetic variables that underlie the origin of these tumors. We developed a novel CNS-PNET mouse model, called CNS-NPCs, using neural progenitor cells derived from human-iPS cells. Through histological, DNA methylation, and RNA sequencing analyses, we find that the CNS-NPC model recapitulates the the morphologic, epigenetic, and transcriptomic features of primary CNS-PNETs. In addition, through in vivo metabolic analyses of CNS-NPCs and the patient derived cell line, PFSK-1, we identified dysregulation in the neurotransmitter...

EPFL2019

Chargement

Novel therapeutic strategies targeting the B-cell receptor signaling and antigen presentation pathways in non-Hodgkin lymphoma

Elena Battistello

B-cell non-Hodgkin lymphomas (B-NHLs) are a heterogeneous group of tumors deriving from the malignant transformation of B cells. The two most common B-NHL subtypes are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which account together for 50-60% of B-NHL cases. The standard of care for advanced or transformed FL and DLBCL is a combination of chemotherapy and the anti-CD20 antibody rituximab (R-CHOP); however, this approach is curative just in a fraction of cases. In addition, despite a good characterization of the genomic lesions present in those tumors, the available targeted therapies are limited and related to only partial responses. Thus, effective and curative treatments for B-NHLs are still missing, imposing the need for the design of new therapeutic strategies for these patients. In this thesis, I characterized the mechanisms of intrinsic and acquired resistance to targeted therapies in B-NHLs and identified novel therapeutic approaches for FL and DLBCL treatment. In the first part of this thesis, I focused on the inhibition of the B cell receptor (BCR) signaling pathway in DLBCL. The propagation of the BCR signal can be blocked using the targeted BTK inhibitor ibrutinib; however, this approach is effective only in a subgroup of DLBCL patients. In my studies, I showed that, in cells intrinsically resistant to ibrutinib, the loss of BTK is compensated by an increased dependency on the PI3K/AKT pathway downstream the BCR. In addition, I proposed to target the SRC kinases which propagate the BCR signal to both BTK and PI3K/AKT, using the new inhibitor masitinib. In cell lines and patients-derived primary samples, I showed that masitinib treatment is effective in both ibrutinib-sensitive and resistant tumors, thus suggesting it as novel therapeutic approach for a broader group of patients. In the second part of this thesis, I characterized the influence of ibrutinib and masitinib treatments on tumor heterogeneity and evolution using single-cells transcriptomics approaches. I showed that, upon long-term targeted treatments, initially sensitive tumors relapse and this is associated with changes in gene expression at the single-cell level. I then identified a set of genes that might contribute to acquired resistance to these drugs. This study will serve as starting point for a broader characterization of the effect of targeted therapies on clonal dynamics and tumor heterogeneity and for the rational design of combinatorial strategies. The last part of this thesis is focused on the characterization of cathepsin S as novel therapeutic target in FL. I showed that, in FL patients, cathepsin S over-activation by a gain-of-function mutation or by gene over-expression promotes lymphomagenesis. I found that cathepsin S has an essential role in regulating the interactions of lymphoma cells with T cells infiltrated in the tumor. Indeed, deletion of cathepsin S leads to a diversification in the repertoire of antigens presented on MHC molecules, which increases tumor immunogenicity. In pre-clinical studies, I showed that cathepsin S inhibition stimulates the activation of a potent anti-tumor immune response and enhances the therapeutic efficacy of current immunotherapies. Thus, inhibition of cathepsin S could represent a novel and promising therapeutic strategy for FL treatment. In follow-up studies, we are identifying specific cathepsin S inhibitors with potential clinical applications.

EPFL2019

Chargement

Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma

Elena Battistello, Giovanni Ciriello, Elie Charles Eugène Dheilly, Maria Christine Donaldson, Natalya Katanayeva, Olivier Michielin, Elisa Oricchio

2018

Chargement

EPFL2019

Novel therapeutic strategies targeting the B-cell receptor signaling and antigen presentation pathways in non-Hodgkin lymphoma

Elena Battistello

EPFL2019