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

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.

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

“…During the past few years, inhibitors of DOT1L have shown potent and selective activity against MLL1-r leukemia [123][124][125]. Indeed, it was recently reported that significant MEIS1 downregulation is a typical result of the DOT1L inhibition [126].…”

Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication

“…In this context, Kühn et al showed in vitro that KMT2A-PTD -mutated cells underwent downregulation of HOXA-cluster, and other MLL target genes followed by cell differentiation, apoptosis and cell death upon DOT1L inhibitor treatment [ 24 ]. The first pre-clinical and clinical results of DOT1L inhibitors in human settings have been encouraging so far, though they have not yet been extensively tested in KMT2A-PTD settings [ 25 , 26 , 27 ]. Other strategies, such as menin-KMT2A inhibitors, also exhibit high efficacy in vitro on a broad range of KMT2A -rearranged AML cell lines [ 28 ].…”

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

“…Despite advances in diagnostic methods and therapeutic effectiveness for AML, refractory acute leukemia still reacts and dies during remission, with limited survival duration. Despite the detection of various genetic alterations, including MLL gene rearrangements, Annalisa reported that the histone methyltransferase DOT1L was active in the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been tested in a clinical trial involving pediatric MLL-r leukemic patients [ 7 ]. Elena found that exposing MLL-AF6-rearranged AML blasts to tipifarnib, a RAS inhibitor, causes cell autophagy and apoptosis, implying that RAS targeting may be a new therapeutic approach for patients with T cell lymphoma (6; 11) [ 8 ].…”