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Molecular Biology Program
 

Kathrin Bernt, Assistant Professor

M.D.


 

 

Contact Info:

Molecular Biology
University of Colorado

Kathrin Bernt, M.D.  Research One North
(RC1-North), Room 4121
Kathrin.Bernt@ucdenver.eduPhone:

 

Our lab is investigating the role of epigenetic gene regulation in normal hematopoietic stem cells and leukemia. There is a growing appreciation that epigenetic mechanisms play critical roles in all aspect of cancer. From a therapeutic standpoint, epigenetic changes in cancer are of particular interest since, in contrast to DNA sequence alterations, they are potentially reversible. We use syngeneic leukemias established in genetic loss of function models combined with genome wide profiling of histone modifications and gene expression to dissect the role of epigenetic modifiers in different molecularly defined types of AML.
 
As one of the first examples of targeted modulation of a leukemogenic program through inhibition or genetic inactivation of an epigenetic modifier,  the H3K79 methyltransferase Dot1l was established as a therapeutic target for the subgroup of leukemias that carry a rearrangement of the Mixed Lineage Leukemia gene, MLL. Methylation of histone 3 at lysine 79  specifically controls a leukemogenic gene expression program in MLL-AF9 fusion driven leukemia cells. Based on this work, a first-in-human clinical trial of a Dot1l small molecule inhibitor is currently underway (http://clinicaltrials.gov/ct2/show/NCT01684150?term=H3K79&rank=1), with the University of Colorado Hospital and Children’s Hospital being sites for the phase I extension.
 
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 in our lab aim at understanding the mechanisms of gene regulation in hematopoiesis and leukemia through methylation of H3K79 and other chromatin modifications.
 
Beyond H3K79 methylation, we are establishing SILAC based histone profiling in malignancies as a means to detect novel epigenetic changes that may potentially be targetable.
Epigenetic changes play a role in a wide variety of cancers and 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.