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Acute myeloid leukemia

Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML

Leukemia volume 32, pages 1124–1134 (2018)Cite this article

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Abstract

The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission. The epigenetic signature, made up of 337 differentially methylated regions, was then integrated with gene and protein expression profiles, leading to a network, where cell-to-cell adhesion and cell-motility pathways were found to be aberrantly activated in relapsed patients. We identified most of these factors as RUNX1-RUNX1T1 targets, with Ras Homolog Family Member (RHOB) overexpression being the core of this network. We documented how RHOB re-organized the actin cytoskeleton through its downstream ROCK–LIMK–COFILIN axis: this increases blast adhesion by stress fiber formation, and reduces mitochondrial apoptotic cell death after chemotherapy treatment. Altogether, our data show an epigenetic heterogeneity within t(8;21)-rearranged AML patients at diagnosis able to influence the program of the chimeric transcript, promoting blast re-emergence and progression to relapse.

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Acknowledgements

This work was supported by grants from CARIPARO Istituto di Ricerca Pediatrica-Fondazione Città della Speranza and Università degli Studi di Padova and from AIRC (Associazione Italiana Ricerca sul Cancro, Special Grant “5xmille”−9962 to FL). We thank Dr. Federica Cattonaro and Dr. Davide Scaglione (IGA Udine, Italy) for RRBS service. We thank Katia Polato, Dr. Anna Leslz, Dr. AnnaMaria Di Meglio, and Dr. Emanuela Giarin for molecular genetic analysis, cytogenetic analysis, and for storing samples of children enrolled in the AML 2002/01 protocol at Hematology-Oncology Clinic at UniPD. Our thanks also to all clinicians working at the participating AIEOP centers.

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    Authors and Affiliations

    1. Istituto di Ricerca Pediatrica (IRP)—Fondazione Città della Speranza, Haematology-Oncology Lab, Padova, Italy

      Matteo Zampini, Elena Manara & Carlo Zanon

    2. Women and Child Health Department, Haematology-Oncology Clinic and Lab, University of Padova, Padova, Italy

      Claudia Tregnago, Valeria Bisio, Giulia Borella, Francesca Zonta, Valentina Serafin, Benedetta Accordi, Barbara Buldini, Giuseppe Basso & Martina Pigazzi

    3. Department of Biology, University of Rome Tor Vergata, Rome, Italy

      Luca Simula & Silvia Campello

    4. Department of Pediatric Haematology and Oncology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

      Luca Simula

    5. IRCCS, Fondazione Santa Lucia, Rome, Italy

      Silvia Campello

    6. Department of Pediatrics, Sant’Orsola Hospital, University of Bologna, Bologna, Italy

      Andrea Pession

    7. Department of Pediatric Onco-Haematology, IRCCS Bambino Gesù Children’s Hospital, University of Pavia, Rome, Italy

      Franco Locatelli

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    Matteo Zampini and Claudia Tregnago contributed equally to this work.

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    Zampini, M., Tregnago, C., Bisio, V. et al. Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML. Leukemia 32, 1124–1134 (2018). https://doi.org/10.1038/s41375-017-0003-y

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