U.S. researchers claim a little-studied RNA-binding regulatory protein known as Musashi 2 and its cellular pathways may represent new therapeutic targets for blood cancers such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The team, headed by scientists at Harvard Medical School and the Whitehead Institute for Biomedical Research, found that Musahi 2 levels were predictive of prognosis in both cancers. High levels of Musashi 2 expression were also associated with increased cell proliferation, decreased cell maturation, and multiple cancer-related cellular pathways in human leukemias.
The findings are published in Nature Medicine, in a paper titled, “Musashi-2 Regulates Normal Hematopoiesis and Promotes Aggressive Myeloid Leukemia.”
Harvard’s Michael Kharas, Ph.D., and the Whithead Institute’s Christopher Lengner, Ph.D., investigated the role of Musashi 2 in established AML and CML cell lines from human patients, and in mouse models of both diseases. They also looked at gene-expression data from 600 AML and CML patients. The cell lines studies confirmed that increased levels of Musashi 2 correlated directly with increased aggressiveness of the cancer. For patients this meant that cancers expressing higher levels of Musashi 2 were associated with poorer outcomes. Conversely, when the amount of Musashi 2 in AML and CML cell lines was reduced the cancers because less aggressive and in some cases even matured and underwent apoptosis.
“Everyone says that human cell lines have nothing to do with human patients,” Dr. Kharas remarks. “But we could go from a mouse, to an in vitro cell culture model, to patient data. And when we saw that you could reduce Musashi 2 in these cell lines and use that information to predict the survival of patients, we were really impressed.”
Drs. Kharas and Lengner point out that although Musashi 2 is known to regulate a self-renewing pathway in stem cells and a cell-proliferation pathway, very little study has been carried out on the protein. In order to see which biochemical pathways Musashi 2 is involved in, the researchers compared gene-expression patterns in human leukemia cells expressing high levels of Musashi 2 with those in which expression of the protein was inhibited. The results suggested that Musashi 2 may play a role in switching on a number of cancer-related pathways, including Wnt, Ras-Mapk and Myc.
“We’ve linked a new gene to the most aggressive leukemias, which is immediately helpful in identifying patients with good and bad prognosis,” states co-author George Daley, Ph.D., who heads Dr. Kharas’ laboratory at the Children’s Hospital Boston. “We are hopeful our new insights into leukemia will help us identify new drug targets.”
The authors stress that Musashi 2 is not sufficient to initiate the development of cancer. However, Dr. Lengner adds, when you add Musashi 2 into the mix, “it makes the cancer more stem cell-like and, as a consequence of that, much more aggressive.”