Targeting DOT1L action and interactions in leukemia: the role of DOT1L in transformation and development.
BACKGROUND
The establishment and maintenance of specialized chromatin is crucial for correct gene expression and chromosome stability in mammalian cells. Therefore, epigenetic insults are frequently observed in cancer. Several chromatin modifying enzymes have been implicated in leukemia, and are attractive candidates for the development of therapeutic agents.


METHODS
The histone methyltransferase DOT1L is responsible for methylation of histone H3 at lysine 79 and is involved in the pathobiology of several leukemias, the majority of which are characterized by chromosomal translocations involving the mixed lineage leukemia (MLL) gene. Leukemic translocations yield fusion proteins involving MLL and other proteins that physically interact with DOT1L. These oncogenic fusion proteins recruit DOT1L to ectopic loci (including HOX gene clusters), whose mis-expression contributes to the transformed phenotype. Studies from stem cells and certain leukemias suggest a second mechanism of leukemogenesis, in which reduced or mistargeted DOT1L activity yields altered centromeric chromatin and consequent chromosomal instability. Targeting DOT1L enzymatic activity as well as interactions with leukemogenic fusion proteins is discussed as possible leads in therapeutic interventions.


RESULTS
In this review, we discuss the normal functions of DOT1L, its mechanistic roles in leukemogenesis, and possible strategies for targeting DOT1L in leukemia. DOT1L is an atypical histone lysine methyltransferase in that it does not contain an enzymatic domain common to all other lysine methyltranferases. This attribute makes DOT1L a unique and specifically targetable enzyme. An emerging role for DOT1L under normal cellular conditions as well as transformed conditions is emerging and shedding light on the biology and mechanisms of some translocation-induced leukemias.


CONCLUSIONS
DOT1L is critical in development, as shown in studies in mouse embryos and embryonic stem cells. DOT1L enzymatic activity is also required for the leukemic transformation capabilities of a number of oncogenic fusion proteins. In addition, interactions between DOT1L and oncogenic fusion proteins are necessary for the transformation process. Therefore, it may be possible to specifically target DOT1L enzymatic activity or DOT1L interactions with leukemogenic fusion proteins.
Barry
Evan R
ER
University of Connecticut, Department of Pharmaceutical Sciences, Unit 3092, 69 North Eagleville Road, Storrs, CT 06269, USA. theodore.rasmussen@uconn.edu
Corry
Gareth N
GN
Rasmussen
Theodore P
TP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase