The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy

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.

Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis

“…These results may account for the reduced responsiveness of EPZ-treated cells against viral infection. An increased expression of TRIM25 in uninfected A549 cells EPZ-treated analyzed by highthroughput RNA sequencing, which was confirmed by qPCR, was previously observed [8]. Collectively, the data indicate that the TRIM25 gene is a target for Dot1L histone methylase.…”

“…Subsequent studies using a chemical inhibitor of Dot1L or specific Dot1L silencers, showed that the downregulation of Dot1L increased influenza virus replication through a decrease of the IFN-β signaling pathway [5]. Conversely, upregulation of Dot1L reduced influenza virus replication [8]. The augmented H3K79 methylation triggered by the influenza virus may increase the IFN-β pathway stimulation and the antiviral response and would represent a host cell defense response to the infection.…”

“…Many of them are factors involved in transcriptional regulation, such as Dot1L, which is frequently found in those complexes [54,55]. The host-factors relevant for infection, such as TRIM25, seem to be a target for Dot1L modulation even in uninfected cells [8]. In agreement with that, an important number of the frequent treatment-emergent adverse events that may be related with infection were reported in Phase 1 clinical trials of MLL-r patients treated with pinometostat (EPZ) [56].…”

“…Further characterization showed decreased nuclear translocation of the NF-kB complex, as well as IFN-β, Mx1 and ISG56 expression in EPZ-treated cells [5] indicating a decreased antiviral type I IFN response, and as a consequence, a stimulation in viral replication. Conversely, Dot1L overexpression reduced the multiplication of the virus [8].…”

“…Further characterization showed decreased nuclear translocation of the NF-kB complex, as well as IFN-β, Mx1 and ISG56 expression in EPZ-treated cells [5] indicating a decreased antiviral type I IFN response, and as a consequence, a stimulation in viral replication. Conversely, Dot1L overexpression reduced the multiplication of the virus [8].Invading viral RNAs are detected by different cytoplasmic sensors that promote type I IFN responses to elicit an antiviral state. Among the cytoplasmic RNA sensors, RIG-I plays a pivotal role in the recognition of negative-strand RNA viruses [9,10].…”