Epigenetic inhibitors in hematological malignancies
In a Hematology-in-Focus session Professor Brian Huntly (University of Cambridge, UK) discussed novel ways to specifically target epigenetic alterations in hematological malignancies. Epigenetic alterations do not change the DNA sequence itself, but affect transcription, translation and possibly also splicing. Epigenetic alterations include modification of histones, DNA methylation, and recently RNA modifications have been described as well. Genes involved in DNA (de)methylation, such as DNMT3A, TET2, and IDH1/2, are often mutated in hematological malignancies.
The majority of AML patients (>70%) carry mutations in epigenetic regulators. MLL fusions are commonly found translocations in AML, in which >80% of the MLL binding partners are members of the chromatin modifying P-TEFb or DOT1L complexes. Inhibitors of DOT1L block the effect of the MLL fusion, switching off critical leukemia genes such as the HOXA cluster.
Other putative epigenetic targets include the histone demethylase LSD1, which maintains AML cells with the MLL-AF9 fusion in an undifferentiated state. An LSD1 inhibitor induced differentiation of AML cells. BET is a regulator of the transcriptional machinery that has been found to be preferentially required for malignant transcription, regulating the expression of critical genes such as MYC and BCL2. Mutations that activate the histone methyltransferase EZH2 have been found in lymphomas, and inhibition of EZH2 reduced proliferation of lymphoma and AML cells.
In phase I clinical studies monotherapy with inhibitors of DOT1L, LSD1 and BET resulted in modest responses. Combinations of treatments, patient selection, and timing of treatment now need to be considered in order to increase efficacy.