Saturday, May 14, 2011

Activating the Notch...

Scientists at the Howard Hughes Medical Institute are studying a signaling pathway that may be related to the onset of various diseases and different types of cancers, among those being leukemia. The Notch signaling pathway is responsible for cell to cell tissue communication in adult and embryonic cells, which regulates gene mechanisms in all metazoans. Notch is a protein that sits on the cell's surface and in response to chemical signals outside of the cell, activates a cascade signal into the cell. Iannis Aifantis, while doing research on this pathway on mice, realized that upon the inhibition of Notch, the mice developed chronic myelomonycitc leukemia (CMML), which is a very uncommon type of cancer in the white blood cells. Ironically, when this pathway is overreactive it will cause the onset of another type of leukemia, T-cell acute lymphoblastic leukemia. In order to test his theory, Aifantis and his colleagues shut down all the bone-marrow notch signaling pathways in mice and the presence of CMML was seen. Amazingly, after re-activating the pathway, the leukemia would disappear completely. In order to see if this worked with humans, he grew a number of human bone marrow stem cells which had ligands that bound to and activated the notch pathway. Surely enough, when notch was deactivated these ligands were shut down and diseases that were precancerous ensued. This research has lead to a new form of targeting myeloid leukemias and drug companies along side of Iannis Aifantis are racing against time to find a drug that can activate the notch signaling pathway.

It is incredible how almost by accident these scientists came across this idea. It seems very interesting to see how a pathway can have such an important impact in ones body and how one mistake in any part of the pathway can lead to a malfunction which then leads to a disease such as cancer (especially after learning about p53 and its role in DNA repair). Although this is a huge step in myeloid cancers, it seems quite a while since a drug will be set in play. The article states that "When dealing with important embryonic signaling pathways such as Notch, however, there’s a fine line between treatment and harm. Because Notch signaling is vital to so many cellular processes, and because over-activation can cause disease, finding a way to nudge its activity in bone marrow stem cells without prompting another type of cancer could be a tricky proposition." Meaning that scientists are going to have to work very carefully and meticulously in order to make a drug that 'fixes' notch, but doesn't lead to another disease/cancer. I question if this pathway when activated fights of myeloid leukemias since upon its activation this type of leukemia totally disappears. Another question I have is wether this a actually a tumor suppressor mechanism because when it is over activated it leads to cancer as well. As many other pathways, it's mechanism isn't known perfectly so we can't conclude anything just yet.

Heres a good website that describes the Notch Pathway Signaling