Understanding functional mechanisms leading to the BILU syndrome

Informazioni relative al progetto

DecipherBILU

ID dell’accordo di sovvenzione: 657633

DOI

10.3030/657633

Progetto chiuso

Data della firma CE 27 Marzo 2015

Data di avvio 1 Maggio 2015

Data di completamento 30 Aprile 2017

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 183 454,80

Contributo UE

€ 183 454,80

Coordinato da

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 1 - DecipherBILU (Understanding functional mechanisms leading to the BILU syndrome)

Periodo di rendicontazione: 2015-05-01 al 2017-04-30

Sintesi del contesto e degli obiettivi generali del progetto

Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders often caused by monogenic mutations that affect normal immune system function or development. PID patients suffer from frequent, severe infections and may also have autoimmune, autoinflammatory or lymphoproliferative manifestation and dysmorphic features. Discovery of the causative mutations helps with the diagnostics of PID patients and may suggest novel avenues for their treatment. Furthermore, studies of PIDs can advance our understanding of the human immune system.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

This project emerged from our finding that a novel mutation is strikingly associated with a rare autosomal dominant primary immunodeficiency that combines B cell Immunodeficiency, Limb abnormalities and Urogenital malformations (BILU syndrome). The mutation is located in a gene encoding a type II topoisomerase (TOP2), an enzyme that regulates DNA topology through the introduction of transient double strand breaks. Functional characterization of TOP2 showed that the causative mutation impaired catalytic activity and stability of the enzyme. Bone marrow analysis of the BILU patient showed a complete absence of CD19+ B cell progenitors, but normal T cell and myeloid progenitors, suggesting that TOP2 is critically important for the early stages of B cell differentiation. We further analysed the role of TOP2 in B cell development and function and discovered that it is critically important for the expression of key transcription factors that are known to drive differentiation towards the B cell lineage. To investigate the emerging role of TOP2 in B cell development we used mass spectrometry and characterised its interactome. We demonstrated that in pro-B cells TOP2 is a part of a multi-protein complex that regulates epigenetic control of gene expression and that its inhibition abrogates expression of the key transcription factors known to regulate B cell fate.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Our work discovered a novel genetic cause for B cell immunodeficiency and revealed a previously unrecognised role of type 2 topoisomerase in cellular commitment to the B cell lineage. These results provide an important breakthrough in the understanding of B lymphocyte development. They also open prospects for future treatment of the BILU patients.

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