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

Xujie Zhao, Ping Wang, Jonathan D. Diedrich, Brandon Smart, Noemi Reyes, Satoshi Yoshimura, Jingliao Zhang, Wentao Yang, Kelly Barnett, Beisi Xu, Zhenhua Li, Xin Huang, Jiyang Yu, Kristine Crews, Allen Eng Juh Yeoh, Marina Konopleva, Chia-Lin Wei, Ching-Hon Pui, Daniel Savic and Jun J. Yang ()
Additional contact information
Xujie Zhao: St. Jude Children’s Research Hospital
Ping Wang: The Jackson Laboratory for Genomic Medicine
Jonathan D. Diedrich: St. Jude Children’s Research Hospital
Brandon Smart: St. Jude Children’s Research Hospital
Noemi Reyes: St. Jude Children’s Research Hospital
Satoshi Yoshimura: St. Jude Children’s Research Hospital
Jingliao Zhang: St. Jude Children’s Research Hospital
Wentao Yang: St. Jude Children’s Research Hospital
Kelly Barnett: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Zhenhua Li: St. Jude Children’s Research Hospital
Xin Huang: St. Jude Children’s Research Hospital
Jiyang Yu: St. Jude Children’s Research Hospital
Kristine Crews: St. Jude Children’s Research Hospital
Allen Eng Juh Yeoh: National University of Singapore
Marina Konopleva: The University of Texas MD Anderson Cancer Center
Chia-Lin Wei: The Jackson Laboratory for Genomic Medicine
Ching-Hon Pui: St. Jude Children’s Research Hospital
Daniel Savic: St. Jude Children’s Research Hospital
Jun J. Yang: St. Jude Children’s Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract FLT3 is 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 of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-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 in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts FLT3 activation and decreases ALL cell sensitivity to FLT3 inhibitor gilteritinib in vitro. In patient-derived xenograft models of ZNF384-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.

Date: 2022
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DOI: 10.1038/s41467-022-33143-w

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