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
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.