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ACUTE MYELOID LEUKEMIA

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia

Leukemia volume 37, pages 571–579 (2023)Cite this article

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Abstract

Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2+ leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2+ leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup.

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Fig. 1: ETO2::GLIS2 induces cell death with CASP3 upregulation mostly via GLIS2 moiety.
Fig. 2: Ectopic ETO2::GLIS2 expression induces CASP3 activation and the intrinsic apoptosis pathway.
Fig. 3: High BCL2 expression and redundancy between BCL2 and MCL1 in ETO2::GLIS2+ leukemic cells.
Fig. 4: Combined BCL2 and MCL1 inhibition synergizes in ETO2::GLIS2 AMKL in vitro.
Fig. 5: Combined BCL2 and MCL1 inhibition abrogates disease development in PDX models.

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Data availability

The RNAseq datasets generated in this study were deposited in Array-Express (E-MTAB-4332 and E-MTAB-12255). Previously published datasets were also used (GSE4119) [54] and (TARGET Data: https://ocg.cancer.gov/programs/target/data-matrix/) [3]. Other data are available from the authors upon reasonable request.

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Acknowledgements

We would like to thank Dr. Olivier Bernard and Dr. Jürg Schwaller for their scientific expertise and for providing essential feedback on this manuscript. We thank Dr. Nicola Salvatore Bertuccio for providing the WSU-AML cell line. This study was supported by Enfants Cancers Santé and clinical partner teams of the Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l’adolescent (SFCE), Sites de Recherche Intégrée sur le Cancer (SIRIC)-SOCRATE (INCa-DGOS-INSERM 12551), Fondation pour la Recherche Médicale (FRM-ING20150532273) and Carnot OPALE. TM is supported by PAIR-Pédiatrie/CONECT-AML (COllaborative Network for Children and Teenagers with Acute Myeloblastic Leukemia: INCa-ARC-LIGUE_11905 and Association Laurette Fugain), Institut National Du Cancer (PLBIO-2014–176 and PLBIO-2018-169), Ligue contre le cancer (Equipe labellisée, since 2016) and Gustave Roussy (PMS CRESCENDO). FP, PA, AP, and TM are members of the OPALE Carnot institute. PA team is also supported by grants from ARC Foundation (Equipe labellisée 2015-2020), the ALF association (2020-2021), INCA (PLBIO-2019-133). TM is a team of the PEDIAC consortium (INCA_15670, www.programme-pediac.com).

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Author notes

  1. These authors contributed equally: Zakia Aid, Elie Robert, Cécile K. Lopez.

  2. These authors jointly supervised this work: Arnaud Petit, Arnaud Jacquel, Thomas Mercher.

Authors and Affiliations

  1. INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France

    Zakia Aid, Elie Robert, Cécile K. Lopez, Fabien Boudia, Melchior Le Mene, Julie Riviere, Marie Baille, Salima Benbarche, Alexandre Fagnan, Cécile Thirant, Laetitia Federici, Muriel Gaudry, Camille Lobry & Thomas Mercher

  2. Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France

    Zakia Aid, Elie Robert, Cécile K. Lopez, Fabien Boudia, Melchior Le Mene, Julie Riviere, Marie Baille, Alexandre Fagnan, Cécile Thirant, Laetitia Federici, Muriel Gaudry & Thomas Mercher

  3. Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, UK

    Cécile K. Lopez

  4. Department of Haematology, University of Cambridge, Cambridge, UK

    Cécile K. Lopez

  5. Team “Myeloid Malignancies and Multiple Myeloma”, Université Côte d’Azur, INSERM U1065/C3M, 06204, Nice, France

    Maxence Bourgoin, Patrick Auberger & Arnaud Jacquel

  6. Unité de Recherche (UMR)-E008 Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, 92260, France

    Laurent Renou & Françoise Pflumio

  7. Unité Mixte de Service - Analyse Moléculaire Modélisation et Imagerie de la maladie Cancéreuse (UMS AMMICA), Gustave Roussy Cancer Campus, 94800, Villejuif, France

    Laure Touchard & Yann Lecluse

  8. Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    Anton Jetten

  9. Gustave Roussy Cancer Campus, Pediatric and Adolescent Oncology Department, INSERM U1015, Université Paris Saclay, 94800, Villejuif, France

    Birgit Geoerger & Arnaud Petit

  10. Pediatric Hematology and Oncology Department, Armand Trousseau Hospital, AP-HP, Sorbonne University, UMRS_938, CONECT-AML, 75012, Paris, France

    Hélène Lapillonne

  11. INSERM U1287, Gustave Roussy Cancer Campus, 94800, Villejuif, France

    Eric Solary

  12. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Soheil Meshinchi & Arnaud Petit

  13. OPALE Carnot Institute, The Organization for Partnerships in Leukemia, 75010, Paris, France

    Françoise Pflumio, Patrick Auberger & Thomas Mercher

  14. INSERM U944, CNRS UMR7212, Institut de Recherche Saint Louis and Université de Paris, 75010, Paris, France

    Camille Lobry

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  1. Zakia Aid
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Contributions

Performed and analyzed experiments: ZA, ER, CKL, MB, FB, LR, AF, CT, LF, JR, MB, LT, YL, ArJ. Performed bioinformatics analyses: ER, CKL, CL. Provided patient samples and clinical information: HP, SM, and AP. Provided major intellectual inputs and/or reagents: SB, ES, MG, BG, AnJ, FP, PA, CL. Drafted the manuscript: CKL, TM. Conceived and supervised the project: CKL, PA, ArJ, TM. All authors revised and approved the final version of the manuscript.

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Correspondence to Cécile K. Lopez, Arnaud Jacquel or Thomas Mercher.

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Aid, Z., Robert, E., Lopez, C.K. et al. High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia. Leukemia 37, 571–579 (2023). https://doi.org/10.1038/s41375-022-01800-0

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