The emerging roles of DOT1L in leukemia and normal development

Abstract

Methylation of lysines within histone proteins represents a posttranslational modification system that can have profound effects on gene expression. An evolutionarily conserved, but poorly understood, histone methylation mark occurs on lysine 79 on histone H3 (H3K79). The H3K79 methyltransferase, DOT1L, is involved in a number of key processes ranging from gene expression to DNA-damage response and cell cycle progression. Recently, DOT1L has also been implicated in the development of mixed lineage leukemia (MLL)-rearranged leukemia, where mistargeting of DOT1L causes aberrant H3K79 methylation at homeobox genes. As DOT1L is essential for leukemic transformation, small-molecule inhibitors of DOT1L function are an attractive therapeutic target for this type of leukemia. However, in order to develop safe treatments, it is necessary to also understand the biological functions of DOT1L. Here we review the various functions of DOT1L in normal mammalian development. Dot1L knockout is embryonic lethal in mice and is important for processes as diverse as proliferation of mouse embryonic stem cells, induced and natural reprogramming, cardiac development and chondrogenesis. Additionally, while an important role for DOT1L in embryonic hematopoiesis is clear, its role in postnatal hematopoiesis is less so. Establishing the precise function of DOT1L in normal adult hematopoiesis and understanding its mode of action will aid in our understanding of the use of DOT1L as a therapeutic target in MLL-rearranged leukemia.

Functional interdependence of BRD4 and DOT1L in MLL leukemia

“…Although the effects of inhibition of BRD4 and DOT1L have generally been best characterized in the MLL-FP leukemias, emerging evidence suggests that therapies against these targets may play a role in other molecular subsets of acute leukemia and indeed other malignancies [46][47][48][49] . The differential sensitivity to these therapies in other cancers is presumably the result of intrinsic differences in the molecular pathogenesis of these diseases as well as the existence of several other protein complexes that lack DOT1L or BRD4 and affect or regulate malignant transcription programs initiated by non-MLL-FP oncogenes 50,51 .…”

Direct screening for chromatin status on DNA barcodes in yeast delineates the regulome of H3K79 methylation by Dot1

“…DOT1L inhibitors have been developed and are currently in clinical trials for the treatment of MLL-r leukemia (Stein and Tallman, 2015). DOT1L has also been implicated in other cancers, and it has a role in normal development and cellular reprogramming (reviewed in McLean et al (2014) and Nguyen and Zhang (2011)). Furthermore, Dot1 plays a role in meiotic checkpoint activation and the DNA damage response (Nguyen and Zhang, 2011).…”

DNMT3A in Leukemia

“…DNMT3A mutants may play a role in up-regulating HOX genes in AML. Novel H3-methyltransferase inhibitors such as DOT1L inhibitors (McLean et al 2014), MLLmenin interaction inhibitors (Borkin et al 2015), and MLL inhibitors (Cao et al 2014) showed efficient knockdown of HOX cluster genes and leukemic cell death, both in vitro and in vivo. Although these compounds were mainly tested in the context of MLL-rearranged leukemia, a wider spectrum of leukemias, including DNMT3A mut AML, may be sensitive to this treatment.…”