H2020Индивидуална стипендия2022–2025

HodgkINsights · Hodgkin Lymphoma: Insights from genomic studies of mutations in coding and non-coding regions

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-07-08 → 2025-07-07
Финансиране от ЕС: 275 210 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните мутации при класическия Ходжкин лимфом, включително тези в протеина STAT6 и в некодиращите части на генома, се анализират за разбиране на развитието на болестта. Това е важно за разработването на нови и по-малко токсични стратегии за лечение на младите пациенти.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Hodgkin Lymphoma: Insights from genomic studies of mutations in coding and non-coding regions

In this project we aim to add insights in the understanding of classical Hodgkin Lymphoma, and in particular on the role of genomic mutations in the pathogenesis. Classical Hodgkin Lymphoma (cHL) accounts for ~15-25% of all lymphomas, and it is one of the most common cancers in adolescent and young adults. Combination chemotherapy, with or without radiotherapy, gives remarkable high 5-years survival rates in young and early-stage cHL patients. However, treatment-related toxicity and long-term morbidity still represent major challenges, especially for young patients. Moreover, a significant percentage of patients relapse or have a refractory disease, and only ~50 % of those can benefit from high-dose chemotherapy treatment and stem cell transplantation. Thus, there is a high demand for novel and less-toxic treatment strategies. In this project we are investigating the role of mutations in a protein, STAT6, frequently mutated in cHL patients. Moreover, we are studying mutations of cHL patients in the non-coding genome, the part of the genome that does not codify for proteins, to understand if also those mutations can be relevant for the disease establishment or progression.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITA DEGLI STUDI DI PERUGIA · PerugiaКоординаторИталия