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; Jun J. Yang

doi:10.1038/s41467-022-33143-w

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, Jun J. Yang

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15 Scopus citations

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.

Original language	English
Article number	5401
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33143-w
State	Published - Dec 2022
Externally published	Yes

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Zhao, X., Wang, P., Diedrich, J. D., Smart, B., Reyes, N., Yoshimura, S., Zhang, J., Yang, W., Barnett, K., Xu, B., Li, Z., Huang, X., Yu, J., Crews, K., Yeoh, A. E. J., Konopleva, M., Wei, C. L., Pui, C. H., Savic, D., & Yang, J. J. (2022). Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia. Nature Communications, 13(1), Article 5401. https://doi.org/10.1038/s41467-022-33143-w

@article{b45a62ca160f44f98ecd56559ccdb293,

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

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.",

author = "Xujie Zhao and Ping Wang and Diedrich, \{Jonathan D.\} and Brandon Smart and Noemi Reyes and Satoshi Yoshimura and Jingliao Zhang and Wentao Yang and Kelly Barnett and Beisi Xu and Zhenhua Li and Xin Huang and Jiyang Yu and Kristine Crews and Yeoh, \{Allen Eng Juh\} and Marina Konopleva and Wei, \{Chia Lin\} and Pui, \{Ching Hon\} and Daniel Savic and Yang, \{Jun J.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33143-w",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Zhao, X, Wang, P, Diedrich, JD, Smart, B, Reyes, N, Yoshimura, S, Zhang, J, Yang, W, Barnett, K, Xu, B, Li, Z, Huang, X, Yu, J, Crews, K, Yeoh, AEJ, Konopleva, M, Wei, CL, Pui, CH, Savic, D & Yang, JJ 2022, 'Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia', Nature Communications, vol. 13, no. 1, 5401. https://doi.org/10.1038/s41467-022-33143-w

TY - JOUR

T1 - Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia

AU - Zhao, Xujie

AU - Wang, Ping

AU - Diedrich, Jonathan D.

AU - Smart, Brandon

AU - Reyes, Noemi

AU - Yoshimura, Satoshi

AU - Zhang, Jingliao

AU - Yang, Wentao

AU - Barnett, Kelly

AU - Xu, Beisi

AU - Li, Zhenhua

AU - Huang, Xin

AU - Yu, Jiyang

AU - Crews, Kristine

AU - Yeoh, Allen Eng Juh

AU - Konopleva, Marina

AU - Wei, Chia Lin

AU - Pui, Ching Hon

AU - Savic, Daniel

AU - Yang, Jun J.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85137866486

U2 - 10.1038/s41467-022-33143-w

DO - 10.1038/s41467-022-33143-w

M3 - Article

C2 - 36104354

AN - SCOPUS:85137866486

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5401

ER -

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

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