Subscribe to RSS
DOI: 10.1055/s-0040-1709788
Overcoming differentiation blockage by inhibition of LSD1 as novel therapeutic strategy in pediatric AML
Recently the lysin-specific histone demethylase 1 (LSD1) has been identified as novel therapeutic target in acute myeloid leukemia (AML), where it is overexpressed in 60 % of patients thereby contributing to the disease defining differentiation blockage. Here, we investigated pharmacological LSD1 inhibition as potential treatment strategy in pediatric AML. LSD1 inhibiton induced cellular differentiation in MLL-rearranged AML, acute megakaryoblastic leukemia with (ML-DS) and without Down syndrome (AMKL) accompanied by impaired proliferation in cell lines and patient-derived cells in vitro. Intriguingly, LSD1 inhibition triggered the JAK-STAT-signaling pathway. Consequently, combination with ruxolitinib, a JAK1/2 inhibitor already used for the treatment of myeloproliferative neoplasms, demonstrated synergistic effects on ML-DS samples, which were shown to frequently harbor mutations within the JAK-STAT pathway. Future in vivo studies accompanied by molecular characterization of the consequences of LSD1 and JAK-STAT inhibition will further help shaping the role of LSD1 as therapeutic target in pediatric AML.
#
Publication History
Article published online:
13 May 2020
© Georg Thieme Verlag KG
Stuttgart · New York