Work

P328: Characterization of a Dux4-r Inhibitor as a Possible Treatment for Acute Lymphoblastic Leukemia

Year: 2023

Type: article

Abstract: Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the major cause of cancer-related death before the age of 20. In up to 10% of cases, the disease is caused by translocation of the double homeobox 4 (DUX4) transcription factor to the immunoglobulin heavy chain (IGH) locus, giving rise to rearranged (DUX4-r) versions, maintaining the DNA binding domain (dbd) of WT DUX4 but with variable C-termini. DUX4-r has transforming ability in cellular and animal models and it is necessary for leukemia maintenance. Through proteomics, we identified a potential DUX4-r inhibitor (iDr) for its ability to bind directly to the DUX4-r DNA-binding domain (dbd). Aims: The aim of this study is to test the inhibitory potential of iDr in cellular and animal models of DUX4-r leukemia. Methods: iDr or its fragments were delivered by means of lentiviral vectors in human leukemia cell lines to test the effects on cell adhesion, proliferation and target gene expression. Overexpression of iDr in human B-ALL patient derived xenograft cells was used to test iDr-dependent effect on PDX cells expansion and leukemia latency in mice. Human markers and GFP expression were monitored over time in peripheral blood (PB) to assess disease progression. Results: We found that iDr and its fragments retaining DUX4-r binding decrease DUX4-r dependent transactivation and targets expression. Intriguingly, iDr selectively blunts DUX4-r leukemia cell adhesion and proliferation, with negligent effect on cells not expressing DUX4-r. In vivo, iDr significantly downregulates DUX4-r targets and reduces leukemia burden delaying the expansion of DUX4-r PDX cells. We are currently testing the effects of a smaller fragment of iDr which retains the inhibitory capacity of DUX4-r. Summary/Conclusion: Delivery of iDr and its fragments retaining DUX4-r binding reduce DUX4-r target gene expression selectively blunting proliferation of cells expressing DUX4-r. Pre-clinical validation of iDr fragments could identify effective therapeutic approaches for the treatment of DUX4-r B-ALL patients. Keywords: Lentiviral transduction, B cell acute lymphoblastic leukemia, Xenotransplantation, ALL

Source: HemaSphere

DOI: 10.1097/01.hs9.0000968224.47489.ef