Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML

Annalisa Lonetti, Valentina Indio, Maria Antonella Laginestra, Giuseppe Tarantino, Francesca Chiarini, Annalisa Astolfi, Salvatore N Bertuccio, Alberto M Martelli, Franco Locatelli, Andrea Pession, Riccardo Masetti

Research output: Contribution to journalArticlepeer-review

Abstract

Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 20 2020

Keywords

  • BRAF
  • ChIP-seq
  • DOT1L
  • Pinometostat
  • Sorafenib
  • pediatric acute myeloid leukemia
  • targeted therapy

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