Abstract
Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.
Highlights
Patients with acute myeloid leukemia frequently present translocations of Mixed Lineage Leukemia (MLL) gene
Infection with either influenza or Sendai viruses stimulated luciferase accumulation in comparison with non-infected cells and pinometostat treatment caused a significant decrease of luciferase accumulation in the infected cells, reinforcing the role of DOT1L in controlling interferon signaling
Pinometostat treated cells during 48 h (EPZ), untransfected cells or cells transfected with the plasmid that expresses His-DOT1L (His-DOT1L) during 48 h, were used to verify DOT1L overexpression and DOT1L enzymatic activity determined by the accumulation of H3K79me[2], as analyzed by immunoflorescence (Fig. 2A) and Western blot (Fig. 2B)
Summary
Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. More than 80 different partner genes have been described to fuse to MLL gene originating different protein complexes Many of these complexes interact with factors involved in transcriptional regulation such as the histone methylase DOT1L that is frequently found in the complexes[6,7]. To characterize the possible contribution of H3K79 methylation to influenza virus control, treatment with pinometostat or/and use of specific lentiviral silencers for DOT1L expression were used. From this study we concluded that methylation of H3K79 by DOT1L has an important role in the control of the interferon signaling and may modulate the infection of different pathogens
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