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Inhibitor of DUX4-IGH to Erase Acute lymphoblastic Leukaemia

Inhibitor of DUX4-IGH to Erase Acute lymphoblastic Leukaemia

Objective

The second most important cause of death and morbidity in Europe is cancer and B-cell acute lymphoblastic leukaemia (B-ALL) is the most common paediatric cancer and cause of cancer-related death before 20 years. In up to 7% of cases, the disease is caused by rearrangements of the genetic regulator DUX4 to the IGH locus, giving rise to the DUX4-IGH fusion. While ectopic expression of DUX4 induces cell death, DUX4-IGH drives transformation. Even though the two proteins share the same DNA binding domain (dbd), DUX4 and DUX4-IGH drive the transcription of non-overlapping target genes. Through proteomics, my lab identified a specific DUX4-IGH inhibitor, which directly binds to DUX4-IGH dbd blocking the activation of target genes. Based on this evidence, the goal of IDEAL is to test the antileukemic activity of the inhibitor in pre-clinical settings.
Using cellular models, I will test the ability of the inhibitor to block transformation driven by DUX4-IGH. I expect to see a significant inhibition of DUX4-IGH driven transformation in the presence of its inhibitor, associated with reduced proliferation, clonogenic and self-renewal potential. To test the efficacy of DUX4-IGH inhibition in leukemia development, I will employ animal models (murine bone marrow transplantation assays and patient derived xenografts of DUX4-IGH B-ALL) and assess disease latency in the presence or absence of the inhibitor. I predict that the inhibitor will block or significantly delay DUX4-IGH B-ALL.
Pre-clinical validation of the DUX4-IGH inhibitor will help defining effective therapeutic strategies for DUX4-IGH B-ALL patients, improving clinical outcome and lowering treatment toxicity, thus overall promoting Europe's healthcare.
Through IDEAL I will expand my expertise in leukaemia research and I will acquire project management and leadership abilities that will foster my personal and professional development as an independent scientist.
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Coordinator

OSPEDALE SAN RAFFAELE SRL

Address

Via Olgettina 60
20132 Milano

Italy

Activity type

Other

EU Contribution

€ 171 473,28

Project information

Grant agreement ID: 841957

Status

Grant agreement signed

  • Start date

    1 February 2020

  • End date

    31 January 2022

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 171 473,28

  • EU contribution

    € 171 473,28

Coordinated by:

OSPEDALE SAN RAFFAELE SRL

Italy