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

Matteo Zampini, Claudia Tregnago, Valeria Bisio, Luca Simula, Giulia Borella, Elena Manara, Carlo Zanon, Francesca Zonta, Valentina Serafin, Benedetta Accordi, Silvia Campello, Barbara Buldini, Andrea Pession, Franco Locatelli, Giuseppe Basso, Martina Pigazzi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalLeukemia
DOIs
Publication statusAccepted/In press - Feb 2 2018

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Acute Myeloid Leukemia
Epigenomics
Recurrence
Stress Fibers
DNA Methylation
Actin Cytoskeleton
Transcriptome
Cell Adhesion
Cell Movement
Cell Death
Drug Therapy
Proteins
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Zampini, M., Tregnago, C., Bisio, V., Simula, L., Borella, G., Manara, E., ... Pigazzi, M. (Accepted/In press). Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML. Leukemia, 1-11. https://doi.org/10.1038/s41375-017-0003-y

Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML. / Zampini, Matteo; Tregnago, Claudia; Bisio, Valeria; Simula, Luca; Borella, Giulia; Manara, Elena; Zanon, Carlo; Zonta, Francesca; Serafin, Valentina; Accordi, Benedetta; Campello, Silvia; Buldini, Barbara; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina.

In: Leukemia, 02.02.2018, p. 1-11.

Research output: Contribution to journalArticle

Zampini, M, Tregnago, C, Bisio, V, Simula, L, Borella, G, Manara, E, Zanon, C, Zonta, F, Serafin, V, Accordi, B, Campello, S, Buldini, B, Pession, A, Locatelli, F, Basso, G & Pigazzi, M 2018, 'Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML', Leukemia, pp. 1-11. https://doi.org/10.1038/s41375-017-0003-y
Zampini, Matteo ; Tregnago, Claudia ; Bisio, Valeria ; Simula, Luca ; Borella, Giulia ; Manara, Elena ; Zanon, Carlo ; Zonta, Francesca ; Serafin, Valentina ; Accordi, Benedetta ; Campello, Silvia ; Buldini, Barbara ; Pession, Andrea ; Locatelli, Franco ; Basso, Giuseppe ; Pigazzi, Martina. / Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML. In: Leukemia. 2018 ; pp. 1-11.
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AU - Simula, Luca

AU - Borella, Giulia

AU - Manara, Elena

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AU - Buldini, Barbara

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