This week we profile a recent publication in Leukemia from the laboratory of Dr. Martin Hirst
at the Centre for High Throughput Biology.
Can you provide a brief overview of your lab’s current research focus?
Mutations in genes encoding epigenetic regulators as well as mutations in the histones they modify are increasingly recognized as drivers of transformation. Mutations in DNA methylation regulators have been identified as frequent early events in the generation of acute myeloid leukemia (AML) clones and are also found at high frequency in expanded, but apparently otherwise normal clones of blood cells in older people. Results from the Cancer Genome Atlas Program also indicate altered methylation patterns of promoter-associated CpG islands to be present in AML genomes. These findings have propelled an exploding interest in understanding how epigenetic perturbations contribute to the development of leukemic cell populations in humans.
The overall objectives of our research are to determine the role that mutations to DNA modifiers play in regulating the suppressed differentiation phenotype of human AML blasts and initiate a preclinical investigation of the use of this knowledge to develop novel, less toxic treatment strategies.
What is the significance of the findings in this publication?
Ascorbic acid (vitamin C) is a well-studied water-soluble essential nutrient and a common medium supplement shown to enhance cellular proliferation. In this publication we report that vitamin C, a cofactor for TET, can reverse the methylation gains characteristic of the IDH1-mutant leukemic blasts in an engineered mouse model and initiate their expression of myeloid markers. These data suggest a new/additional role of TET/IDH mutations in driving an epigenetic-mediated silencing of regulatory elements required to activate myeloid differentiation. They also show this mechanism can be readily reversed by exposing the affected cells to a known, nontoxic molecule (vitamin C). These findings raise the exciting possibility that this type of epigenetic change may constitute a more generalized mechanism contributing to the blocked differentiation phenotype of human AML blasts and one that may be targeted by strategies that have significantly reduced side effects.
What are the next steps for this research?
Having established that vitamin C induces specific epigenetic reprogramming in an engineered murine leukemic model we are now positioned to exploit vitamin C as a tool to dissect the molecular and functional impacts of TET2 disruption in a leukemic context. These studies will be extended to engineered human models and patient derived xenografts that form the basis for experiments designed to assess clinical translation.
This research was supported by:
We gratefully acknowledge support of the Terry Fox Research Institute, the Canadian Cancer Society Research Institute and the Canada Foundation for Innovation
