Previously published in At The Forefront, June 7, 2019
It all started with a simple question: “How do cells communicate with the outside world to sense their environment?”
The pursuit of the answer turned out to reveal far more than what Amittha Wickrema, PhD, professor of medicine at the University of Chicago, had dreamed. Focusing on how the production of red blood cells is triggered, Wickrema and his long-time collaborators Amit Verma, MD, from Albert Einstein College of Medicine and Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago, identified a key protein that could serve as a drug target to cure a group of blood diseases.
Like all other types of cells, blood cells are produced by stem cells. Upon receiving special molecular signals known as cytokines, these impressionable stem cells start to differentiate into various types of blood cells. The process seems straightforward enough, until you consider the large diversity and immense number of blood cells in our bodies. In the case of red blood cells, the production can exceed a rate of one billion cells per minute. Any flaws in the regulation of this process can have dire consequences. If the generation of these cells spirals out of control, the result is blood cancer; a dramatic decline in the production leads to anemia.
Pre-cancerous blood diseases associated with the overproduction of blood cells are often treated by targeting the mutated Janus kinase 2 (JAK2) protein, which is essential for cell growth and division. JAK2 resides in the cell and is activated when exterior cytokines bind to the cell surface.
“There is a whole group of blood diseases where JAK2 is mutated, leading to the overproduction of red blood cells,” Wickrema said. “Unfortunately, JAK2 drugs do not permanently eliminate the cells carrying mutant JAK2 and hence aren’t a cure.”
Until recently, the interconnectedness between JAK2, cytokines, and the DNA in the nucleus for blood cell production remained an enigma. In a new study published in the June 2019 issue of Cancer Discovery, Wickrema and his coauthors were the first to complete this connection by identifying a crucial second protein in this communication pathway, the TET methylcytosine dioxygenase 2 (TET2).
TET2 directly communicates with the DNA in the nucleus, and it can be indirectly activated by cytokines through the JAK2 protein. Where the JAK2 drug falls short in regulating blood cell production, now drugs tailored towards TET2 activation may compensate—with perhaps greater effectiveness. Given TET2’s direct interaction with the DNA in the nucleus, “TET2 drugs may give a more direct access to gene activation, and TET2’s more downstream role can perhaps provide us with greater control over the production of blood cells,” Wickrema said.