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

Projektinformationen

HodgkINsights

ID Finanzhilfevereinbarung: 101032145

DOI

10.3030/101032145

Projekt abgeschlossen

EK-Unterschriftsdatum 19 April 2021

Startdatum 8 Juli 2022

Enddatum 7 Juli 2025

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 275 209,92

EU-Beitrag

€ 275 209,92

Koordiniert durch

UNIVERSITA DEGLI STUDI DI PERUGIA
Italy

Periodic Reporting for period 1 - HodgkINsights (Hodgkin Lymphoma: Insights from genomic studies of mutations in coding and non-coding regions)

Berichtszeitraum: 2022-07-08 bis 2025-07-07

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We have identified the genomic sequences and the locations bound by the mutated transcription factor STAT6 in several cHL cell lines, and several gene networks specifically altered by mutants STAT6. Interestingly, we have uncovered that STAT6 mutants binds and deregulates several important genes known to be involved in cHL pathogenesis. For example they upregulate the expression of genes for some chemokines and receptors involved in pro-survival signals, and some proteins with immuno-suppressive functions, while they downregulate some tumor suppressors known to be involved in haematological malignencies. We have found that the binding of STAT6 mutants drives local epigenetic chromatin changes, and activates genomic regions that are normally less accessible for transcription, which in turn results in deregulation of some relevant genes for cHL. We have also identified some newly formed long-range chromatin interactions in proximity of STAT6 mutants binding, confirming that the mutants are able to bind different regions not bound by the STAT6 wild type protein, which directly drive chromatin rearrangements that impact gene transcription of the nearby genes, including some known to be important for cHL cells survival.

Moreover, we have mapped the regions outside the genes (non-coding genome) which have regulatory function in gene transcription (promoters, enhancers, superenhancers) in 10 cHL cell lines, and evaluated their activation state. This allowed us to build a cathalog of important functional non-coding regions that could be interested by mutations affecting their function, and so that could have important role in the pathogenesis. We are now selecting mutations found in these regulatory non-coding regions of samples from cHL patients that we have sequenced, to identify some recurrent ones to investigate.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The insights about the aberrant gene programs regulated by STAT6 mutants is of fundamental importance to understand the biology of cHL and other lymphomas in which those mutations have been found. Demonstrating a role for mutants STAT6 in the pathology could lead to the clinical development of Jak-STAT inhibitors as treatment in patients with such mutations, but also pave the way for treatments directed against specific pathways deregulated by mutants STAT6.

For the second part of the project, we aim to identify mutations in the non-coding genome that could affect the function of regulatory elements such as enhancers, superenhancers or promoters, and underly potentially relevant mechanisms of pathogenesis. Those mechanisms could explain the peculiarities of Hodgkin Lymphoma, which have been not explained so far by mutations found in regions codifying genes, and that are mostly shared with other lymphoma. Moreover, uncovering such mechanisms could provide new potential targets for therapeutic treatments.

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