Deciphering translocation-based genome topology effects and their role in lymphoma formation

Descripción del proyecto

Traslocaciones cromosómicas y función nuclear

El cáncer suele asociarse con traslocaciones cromosómicas, un fenómeno en el que un cromosoma se rompe y sus fragmentos se adhieren a otro cromosoma. Esto puede interrumpir genes supresores de tumores o, con mayor frecuencia, dar lugar a genes de fusión o protooncogenes en el punto de interrupción de la traslocación, lo que causa la oncogénesis. La hipótesis de trabajo del proyecto LymphoTOP, financiado con fondos europeos, es que las traslocaciones cromosómicas perturban la estructura del genoma y pueden provocar una desregulación adicional. Los investigadores se centrarán en el linfoma no Hodgkin y determinarán cómo pueden afectar las traslocaciones en los genes de la inmunoglobulina al panorama genómico y epigenético, y conducir a la enfermedad. Los resultados proporcionarán conocimientos esenciales sobre la función nuclear y la carcinogénesis.

Objetivo

A central goal in cancer research is to identify the molecular mechanisms underlying tumor formation, such as translocations that result in expression of fusion genes or proto-oncogenes located at the translocation breakpoints. While the consequences of this erroneous expression have been widely studied, other effects of translocations remain largely unexplored. Nevertheless, these can provide vital new insights into tumorigenesis. I hypothesize that translocations disturb the global 3D genome architecture, causing alterations in chromosome territory positioning and interchromosomal interactions. And, that these can account for (in)activation of key genomic loci for which the cause of deregulation remains so far unknown. I will address this hypothesis in the context of Non-Hodgkin lymphoma (NHL)-related immunoglobulin (IGH) translocations. By genome editing we will create lymphoblastoid cell lines and cord blood cell-derived B lymphocytes in which IGH translocation-based effects can be cleanly dissected in vitro and in vivo. In these models, we will study how IGH translocations affect genome topology, the epigenetic and gene expression landscape and NHL formation. To that end, we will assess (i) chromosome territory structure and interchromosomal crosstalk by chromatin conformation capture and fixed- and live-cell imaging, (ii) epigenetic and gene expression maps using bulk and single-cell profiling and (iii) in vivo tumor formation. Importantly, after exploring the presence of the observed gene expression changes in NHL samples, we will target the coinciding changes in in vitro and in vivo approaches to probe their relevance for lymphomagenesis. Overall, LymphoTOP shall lead to deeper insights into translocation-based genome topology reorganisation and its role in tumorigenesis, and to potential identification of new vulnerabilities of lymphomas. Thus, extending its impact to many fields, from lymphoma and tumor biology to 3D genome organisation and beyond.