The primary interest of the Bernt lab lies in investigating the role of epigenetic gene regulation in normal hematopoietic stem cells, and extending these relevant findings to the study of leukemia. Epigenetic changes in cancer are of particular interest since, in contrast to DNA sequence alterations, they are potentially reversible.
As one of the first examples of targeted modulation of a leukemogenic program through inhibition or genetic inactivation of an epigenetic modifier, Dr. Bernt was able to demonstrate that methylation of histone 3 at lysine 79 specifically controls a leukemogenic gene expression program in MLL-AF9 fusion driven leukemia cells (Bernt... Armstrong, Cancer Cell 2011). This established the H3K79 methyltransferase Dot1l as a therapeutic target for the subgroup of leukemias that carry a rearrangement of the Mixed Lineage Leukemia gene, MLL.
Based on this work, phase I/II clinical trials
of a Dot1l small molecule inhibitor are currently underway in both adults and
children. Both trials are open at UC Denver (University of Colorado Hospital
and Children's Hospital Colorado).
While it is clear that H3K79 methylation is critically important for MLL-rearranged leukemia, the role of this modification in normal hematopoiesis or other leukemias is not well defined. In addition, the downstream molecular pathways are largely unknown. Further studies aim at understanding the mechanisms of gene regulation in hematopoiesis and leukemia through methylation of H3K79 and other chromatin modifications.
There is a growing appreciation that epigenetic changes play a role in a wide variety of cancers and may govern biological processes associated with relapse and refractory disease. Our goal is to develop the depth of mechanistic understanding that will allow targeted pharmacologic modulation of epigenetic states as a means to develop more specific, more effective, and better tolerated therapies for our patients.