Dissemin is shutting down on January 1st, 2025

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Nature Research, Nature Communications, 1(13), 2022

DOI: 10.1038/s41467-022-33143-w

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Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

Abstract

AbstractFLT3is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression ofFLT3inZNF384-rearranged ALL, consistently across cases harboring different fusion partners withZNF384. Mechanistically, we discover an intergenic enhancer element at theFLT3locus that is exclusively activated inZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome inZNF384-rearranged ALL cells. Downregulation ofZNF384bluntsFLT3activation and decreases ALL cell sensitivity to FLT3 inhibitor gilteritinib in vitro. In patient-derived xenograft models ofZNF384-rearranged ALL, gilteritinib exhibits significant anti-leukemia efficacy as a monotherapy in vivo. Collectively, our results provide insights into FLT3 regulation in ALL and point to potential genomics-guided targeted therapy for this patient population.