Descripción del proyecto
Estudios genómicos de la biología del linfoma de Hodgkin
El linfoma de Hodgkin (LH) es una de las neoplasias malignas más comunes en adultos jóvenes. El estudio de los mecanismos que subyacen a la biología de los linfocitos B anormales del LH puede ayudar a desarrollar mejores tratamientos. En el proyecto HodgkINsights, financiado por las Acciones Marie Skłodowska-Curie, se estudiará la función de las mutaciones en el dominio de unión a ADN del factor de transcripción STAT6, identificado con anterioridad como la alteración genética típica en el LH. El equipo llevará a cabo una inmunoprecipitación de cromatina y una secuenciación del ARN hologenómicos, lo que permitirá dilucidar la regulación y la presencia de la expresión génica aberrante por parte del STAT6 mutante en estirpes celulares del LH frente a estirpes celulares del linfoma no hodgkiniano, así como a investigar las consecuencias funcionales a nivel celular. Por últimos, se emplearán tecnologías de modificación del genoma para evaluar cómo las mutaciones identificadas pueden alterar las redes reguladoras críticas para la biología de LH.
Objetivo
Classical Hodgkin Lymphoma (cHL) is one of the most common cancers in young adults. While chemo-radiotherapy is effective, many patients continue to die of cHL or to suffer long-term treatment toxicities, such that more effective and less toxic drugs are needed. Studying the mechanisms underlying the puzzling biology of cHL (the only B cell-derived lymphoma loosing its B-cell identity) should illuminate its pathogenesis and possibly aid in developing better therapeutic strategies. In this project, I will study the function of mutations in the DNA binding domain of the STAT6 transcription factor, which the host laboratory identified as one of the most frequent genetic lesions in cHL. I will perform genome-wide ChIP- and RNA-seq studies to uncover aberrant gene expression regulation and occupancy by mutant versus wild-type STAT6 in cHL versus non-Hodgkin lymphoma (NHL) cell lines, and investigate their functional consequences at the cellular level. I will then express mutant STAT6 in germinal center (GC) B cells, the cHL cell of origin, to evaluate their role in early lymphomagenesis. Because genes mutated in cHL greatly overlap with those altered in NHLs, from which cHL is strikingly different, I will also explore whether unidentified mutations in non-coding regulatory regions may underlie the peculiar cHL pathogenesis. Recurrent somatic non-coding mutations will be identified through whole-genome sequencing of primary cases and will be annotated to the non-coding elements specifically active in cHL cell lines, which I will identify through RNA- and ChIP-seq for key histone marks. Finally, I will use appropriate techniques (e.g. genome topology and CRISPR editing) to assess how such mutations may alter regulatory networks important for cHL biology and identity. The project will also expand my expertise in genomic regulation in lymphomas, boost my research productivity after a career break, and support my transition to an independent investigator.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
06123 Perugia
Italia