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Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis

Project description

Molecular insight into acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia is a common paediatric malignancy caused by the transformation of B lymphocytes. To provide a better understanding of the disease's underlying mechanisms, the EU-funded SirT-IMLEU project will study the process of B cell maturation. Scientists will focus on the SIRT7 gene, a key player in genome homeostasis, and PAX5, a transcription factor required for B cell development. They will decipher the role of SIRT7 in PAX5-associated transcription and the functional interplay between these two molecules in leukaemic cells. The project's findings are expected to highlight the restoration of PAX5 protein levels as a clinical intervention for the cure of this disease.

Objective

Acute lymphoblastic leukemia, the most common pediatric cancer, originates in many cases from the malignant transformation of a developing Blymphocyte in the bone marrow. Understanding the mechanisms of B cell maturation and how their perturbation contributes to the onset of this pathology is essential for evolving improved strategies for those patients not responding to current therapies. Importantly, this project aims to discover novel mechanisms of B lymphopoiesis by studying the interplay between SIRT7, a Sirtuin family member critical for genome homeostasis, and PAX5, a transcription factor required for B cell development and to sustain B cell identity. Sirtuins play key roles in the maintenance of genome integrity under stress and their deficiency has been linked to the pathogenesis of cancer. Importantly, SIRT7 is highly expressed in developing lymphocytes yet their role in immune cells and its relationship with leukemia awaits further investigation. With this project, we will define SIRT7-dependent regulatory mechanisms of PAX5 protein turnover, its relationship with PAX5-associated transcriptional programs and how their functional interplay is abnormal in leukemic cells. Because PAX5 is found in haploinsufficiency in most of the cases of acute lymphoblastic leukemia of B-cell progenitors, the development of this project is highly significant to the society as it has the potential to generate novel approaches to restore PAX5 protein levels, with important implications for clinical interventions and the cure of this disease.

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Topic(s)

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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-2019

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Coordinator

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS
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.

€ 172 932,48
Address
CARRETERA DE CAN RUTI CAMI DE LES ESCOLES S/N
08916 Badalona
Spain

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Region
Este Cataluña Barcelona
Activity type
Research Organisations
Links
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.

€ 172 932,48
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