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

Author

Listed:
  • 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
    St. Jude Children’s Research Hospital)

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.

Suggested Citation

  • 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 & Kristin, 2022. "Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33143-w
    DOI: 10.1038/s41467-022-33143-w
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    References listed on IDEAS

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    1. Thomas B. Alexander & Zhaohui Gu & Ilaria Iacobucci & Kirsten Dickerson & John K. Choi & Beisi Xu & Debbie Payne-Turner & Hiroki Yoshihara & Mignon L. Loh & John Horan & Barbara Buldini & Giuseppe Bas, 2018. "The genetic basis and cell of origin of mixed phenotype acute leukaemia," Nature, Nature, vol. 562(7727), pages 373-379, October.
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