期刊
CANCERS
卷 12, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cancers12071972
关键词
pediatric acute myeloid leukemia; DOT1L; ChIP-seq; BRAF; targeted therapy; Pinometostat; Sorafenib
类别
资金
- Associazione Italiana per la Ricerca sul Cancro [MFAG2016, 19117]
- Pezcoller Foundation, Trento, Italy
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, includingMLLgene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation ofMLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatricMLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lackingMLL-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 ofMLL-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 ofMLL-r, including the Sorafenib targetBRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.
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