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ACUTE MYELOID LEUKEMIA

FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia

Leukemia volume 38, pages 291–301 (2024)Cite this article

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Abstract

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

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Fig. 1: EZH2 is downregulated by FLT3 inhibition in AML cell lines.
Fig. 2: EZH2 is downregulated by FLT3 inhibition in primary AML.
Fig. 3: FLT3i induce EZH2 protein instability.
Fig. 4: FLT3i reduce H3K27me3 at PRC2 target genes.
Fig. 5: FLT3i increase expression of PRC2 target genes.
Fig. 6: FLT3i and PRC2i promote myeloid differentiation in murine and human AML.
Fig. 7: FLT3i and PRC2i reduce leukemic burden and promote differentiation in vivo.

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Data availability

Mass spectrometry raw files generated in this study are publicly available in the Chorus repository (www.chorusproject.org) at the project number 1806. Analyzed data from proteome, ChIP sequencing, and RNA sequencing studies are available in the supplemental files. Raw ChIP-seq files were deposited to GEO (GSE243857).

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Acknowledgements

Shared Resources at Roswell Park Comprehensive Cancer Center were supported by the National Cancer Institute Cancer Center Support Grant 5P30 CA016056 and R50 CA211108. This work was supported by National Institutes of Health grants (R21 CA198621, K08 CA230190, R37 CA226433, and T32 HL007439-36) and the Biff Ruttenberg Foundation. Dr. Sung received additional support from Benjamin and Mary Siddons Measey Foundation, American Society of Hematology, the Leukemia & Lymphoma Society, and the Roswell Park Alliance Foundation. Dr. Carroll receives support from Veterans Administration Merit Award I01BX004662.

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Authors and Affiliations

  1. Department of Medicine – Leukemia, Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Pamela J. Sung, Murugan Selvam, Katie Bryant & Lucie Pham

  2. Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

    Pamela J. Sung, Bryan Manning & Martin Carroll

  3. Department of Pediatrics, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine and Abramson Cancer Center, Philadelphia, PA, USA

    Simone S. Riedel & Kathrin M. Bernt

  4. Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Hongbo M. Xie

  5. Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Gerald B. Wertheim

  6. Department of Biochemistry and Biophysics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

    Katarzyna Kulej, Benjamin A. Garcia & Simone Sidoli

  7. Department of Cancer Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

    Robert L. Bowman

  8. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Jennifer Peresie & Michael J. Nemeth

  9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ross L. Levine

  10. Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, USA

    Benjamin A. Garcia

  11. Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA, USA

    Sara E. Meyer

  12. Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA

    Simone Sidoli

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Contributions

PJS and MC designed all experiments, interpreted all data, and wrote the manuscript. SS, KK, and BAG performed and analyzed proteomic experiments. SSR, HMX, and KMB performed and analyzed ChIP-Seq experiments. KMB provided intellectual input and experimental guidance on functional genomics. KB and BM performed trametinib experiments and assisted with animal studies. MS and LP performed experiments for revisions. GW performed pathology assessment of murine histology. RLB and RLL provided Flt3ITD Npm1c AML cells and experimental guidance. JP and MJN developed the spectral flow cytometry panel and assisted with analysis. SEM provided Flt3ITD Dnmt3aKO mice and experimental guidance. All authors reviewed and approved the manuscript.

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Correspondence to Pamela J. Sung.

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Competing interests

PJS, MS, SSR, HMX, KB, BM, GBW, LP, KK, JP, MJN, BAG, and SS declare no relevant competing interests. RLB has received honoraria from Mission Bio and is a member of the Speakers Bureau for Mission Bio. RLL is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Bakx, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, and Isoplexis. RLL received research support from Abbvie, constellation, Ajax, Zentalis, and Prelude. RLL has received research support from and consulted for Celgene and Roche and has consulted for Syndax, Incyte, Janssen, Astellas, Morphosys, and Novartis. RLL has received honoraria from Astra Zeneca and Novartis for invited lectures and from Gilead and Novartis for grant reviews. SEM received research funding from CellCentric. KMB has received research funding from Syndax Pharmaceuticals, Inc. MC is on the Scientific Advisory Board for Cartography Biosciences.

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Sung, P.J., Selvam, M., Riedel, S.S. et al. FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia. Leukemia 38, 291–301 (2024). https://doi.org/10.1038/s41375-023-02131-4

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