The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy
Laura Marcos-Villar1,2, Amelia Nieto3,4
1Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Cantoblanco, 28049, Madrid, Spain. lmarcos@cnb.csic.es.
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.
Insights
DOT1L inhibition, a potential treatment for MLL-r leukemia, may increase infection risk by impairing the innate immune response. Patients treated with DOT1L inhibitors require close monitoring for infections.
Area of Science:
- Oncology
- Virology
- Epigenetics
Background:
- Acute myeloid leukemia (AML) often involves MLL gene translocations, leading to MLL-rearrangements (MLL-r).
- MLL-r complexes frequently include DOT1L, a histone methyltransferase, causing aberrant histone methylation and impacting gene expression.
- Pinometostat, a DOT1L inhibitor, shows therapeutic promise in MLL-r leukemia clinical trials.
Purpose of the Study:
- To investigate the role of DOT1L in the host innate immune response to viral infections.
- To assess the impact of DOT1L inhibition on viral replication and host defense mechanisms.
- To explore potential implications for MLL-r leukemia patients undergoing pinometostat treatment.
Main Methods:
- Studied the effect of DOT1L inhibition and down-regulation on viral replication (influenza, vesicular stomatitis, Sendai viruses).
- Analyzed gene expression changes in human lung epithelial cells treated with pinometostat.
- Examined the deregulation of innate immune response genes (RUBICON, TRIM25, BCL3) and let-7B microRNA.
Main Results:
- DOT1L inhibition reduced Sendai virus-induced innate response and decreased influenza virus multiplication.
- Overexpression of DOT1L decreased influenza virus multiplication.
- Pinometostat treatment deregulated key innate immune genes and let-7B microRNA in lung epithelial cells.
Conclusions:
- DOT1L plays a significant role in regulating the host innate immune response against viral pathogens.
- Deregulation of innate immune genes and let-7B by pinometostat may contribute to its therapeutic effects in MLL-r leukemia.
- MLL-r leukemia patients treated with pinometostat may have increased susceptibility to infections, necessitating careful monitoring.
