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

Project description

Genomic studies of Hodgkin’s lymphoma biology

Hodgkin’s lymphoma (HL) is one of the most common cancers in young adults. Studying the mechanisms underlying the biology of HL abnormal B cells may aid in the development of better therapeutic strategies. Funded by the Marie Skłodowska-Curie Actions programme, the HodgkINsights project will study the function of mutations in the DNA binding domain of the STAT6 transcription factor, previously identified as a typical genetic lesion in HL. Application of genome-wide chromatin immunoprecipitation- and RNA-sequencing will uncover aberrant gene expression regulation and occupancy by mutant STAT6 in HL versus non-HL cell lines and help investigate functional consequences at the cellular level. Finally, genome-editing technologies will be used to assess how identified mutations may alter regulatory networks critical for HL biology.

Objective

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.

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Keywords

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2020

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Coordinator

UNIVERSITA DEGLI STUDI DI PERUGIA
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 275 209,92
Address
PIAZZA DELL UNIVERSITA 1
06123 Perugia
Italy

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Region
Centro (IT) Umbria Perugia
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 275 209,92
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