Therapeutic strategies against hDOT1L as a potential drug target in MLL-rearranged leukemias

Abstract

Therapeutic intervention of proteins participating in chromatin-mediated signaling with small-molecules is a novel option to reprogram expression networks for restraining disease states. Protein methyltransferases form the prominent family of such proteins regulating gene expression via epigenetic mechanisms thereby representing novel targets for pharmacological intervention. Disruptor of telomeric silencing, hDot1L is the only non-SET domain containing histone methyltransferase that methylates histone H3 at lysine 79. H3K79 methylation mediated by hDot1L plays a crucial role in mixed lineage leukemia (MLL) pathosis. MLL fusion protein mediated mistargeting of DOT1L to aberrant gene locations results in ectopic H3K79 methylation culminating in aberrant expression of leukemogenic genes like HOXA9 and MEIS1. hDOT1L has thus been proposed as a potential target for therapeutic intervention in MLL. This review presents the general overview of hDOT1L and its functional role in distinct biological processes. Furthermore, we discuss various therapeutic strategies against hDOT1L as a promising drug target to vanquish therapeutically challenging MLL.

Keywords: Chromatin; DNA repair; Gene expression; Histone methylation; Histone methyltransferases; Mixed lineage leukemia.

Fig. 1

Role of hDot1L in MLL related leukemogenesis. a MLL gene, which normally codes for H3K4 methyltransferase, undergoes chromosomal translocations and gets fused to more than 50 recurrent MLL translocation partners. These fusion partners interact with hDot1L and lead to mistargeting of hDot1L to MLL target genes like Hox gene cluster. Ectopic H3K79 methylation and the subsequent activation of the target genes results in leukemogenesis. b Small molecules that are capable of inhibiting the HMTase activity of would block H3K79 methylation and subsequent inhibition of leukemogenesis. c Another therapeutic strategy would be modulators that block the interaction of hDot1L with MLL fusion proteins. This would prevent ectopic H3K79 methylation and may lead to a novel treatment for MLL-related leukemogenesis. d Ectopic H3K79 methylation levels could be prevented by increasing the stability of untranslocated MLL1, thereby replacing the MLL-fusion chimeras

Fig. 2

Combination of hDot1L inhibitors with other agents. EPZ-5676 (DOT1L inhibitor) in conjunction with standard of care drugs for AML (cytarabine and daunorubicin) and DNA hypomethylating agents (azacitidine and decitabine) showed synergistic antiproliferative effect against MLL-rearranged leukemic cells. Monotherapy involving only hDot1L inhibitors showed only modest effect as indicated by single arrows in case of EPZ-5676 and EPZ004777. Moreover, another inhibitor of hDot1L (EPZ004777) in combination with MLL-Menin interaction inhibitor (MI-2-2) also showed synergistic growth inhibitory effects in the MLL-rearranged leukemias. The synergistic therapeutic effect is denoted by small multiple arrows in cases involving combined treatment