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Salome', M.1; Caronni, C.1; Runfola, V.1; Giambruno, R.1; Campolungo, D.1; Ghirardi, C.1; Gabellini, D.1

doi: 10.1097/01.HS9.0000564892.23559.d7
Publication Only: Acute lymphoblastic leukemia - Biology & translational research

1Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy

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B cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer and the major cause of cancer-related death before the age of 20. In up to 7% of cases, the disease is caused by rearrangements of the Double Homeobox 4 (DUX4) transcription factor to the immunoglobulin heavy chain (IGH) locus, giving rise to the oncogenic fusion protein DUX4-IGH. While ectopic expression of wild type DUX4 induces apoptosis, DUX4-IGH has transforming ability in cellular and animal models. These opposite biological activities are mirrored by the ability of DUX4 and DUX4-IGH to drive the transcription of non-overlapping sets of target genes, despite the two proteins share the same DNA binding domain (dbd).

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Through proteomics, we identified a specific DUX4-IGH inhibitor. Preliminary data indicate that the inhibitor directly binds to DUX4-IGH dbd blocking the activation of target genes. Based on this evidence, I aim to test the antileukemic activity of the inhibitor.

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Human cell lines and primary murine bone barrow progenitor cells will be lentivirally transduced to induce the expression of DUX4-IGH alone or in combination with its inhibitor, and the effects on proliferation, transformation, clonogenic potential and self-renewal ability in B-cell differentiation conditions will be evaluated.

To test the efficacy of DUX4-IGH inhibition in leukemia development, I will employ 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 DUX4-IGH inhibitor.

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Preliminary data indicate that the activity of DUX4-IGH is restricted to B-cells, supporting the need of a B-cell specific co-factor. Importantly, lentiviral expression of the DUX4-IGH inhibitor in NALM6 cells that carry a DUX4-IGH translocation reduce the endogenous levels of DUX4-IGH targets.

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 in cell culture systems. I predict that the inhibitor will rescue differentiation potential and block or significantly delay leukemia development in mice injected with DUX4-IGH expressing pro-B cells.

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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.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.