Each year, some 29,000 adults and 2,000 children are diagnosed with leukemia, a
form of cancer that is caused by the abnormal production of white blood cells in the
bone marrow. Current treatments rely primarily on killing the cancer cells, which
also destroys normal cells. But what if a way could be found to reprogram cancerous
cells back into normal cells? A team of Syracuse University researchers believes it
may have found a way to do just that.
Led by Michael Cosgrove, assistant professor of biology in SU's College of Arts and
Sciences, the team discovered a way to disrupt the protein switch that is a critical
component in the process to create white blood cells. Its discoveries could lead to a
more effective way to treat some forms of leukemia and revolutionize the approach to
treating other forms of cancer. The research was recently published online in the
prestigious Journal of Biological Chemistry of the American Society for Biochemistry
and Molecular Biology, and is forthcoming in the print edition.
"We believe our discovery is just the tip of the iceberg," Cosgrove says. "Our hope is
that from the knowledge we have gained in understanding how these proteins work
in normal cells, we will be able to find new ways to treat all types of leukemia. We
also think the discoveries will have broad implications in treating other types of
cancer."
To understand how white blood cells are produced, one must begin by looking at the
genetic code, the DNA, which provides the blueprint for all the life processes that are
carried out in cells throughout the body. All of the cells in the body begin as stem
cells with the same DNA. If stretched out in one continuous strand, this genetic
blueprint would be about two meters long (about six feet), yet cells somehow manage
to compact this rather long DNA strand into its nucleus without tangling or
disrupting the exact DNA sequence. "It's sort of like stuffing 10,000 miles of spaghetti
into a basketball without it tangling or breaking," Cosgrove says. What differentiates
a liver cell from a blood cell is how that DNA is compacted or packaged in the cell
nuclei, which results in different genes being expressed and leads to the production of
specialized cells (white blood cells, liver cells, pancreatic cells, etc.). Proteins control
this DNA packaging process.
Cosgrove's research team has spent the past three years studying one of the proteins
that regulate the way DNA is packaged when white blood cells are formed. The
protein is called the Mixed Lineage Leukemia (MLL) protein. In normal cells, the
MLL protein, which contains 3,969 amino acids, combines with three other proteins
to create a molecular switch that controls the DNA packaging events required for the
formation of white blood cells. In some types of leukemia, the MLL switch is broken,
which prevents white blood cells from maturing properly, resulting in a dangerous
proliferation of immature white blood cells.
Cosgrove's team identified a tiny component of the MLL protein-a peptide
sequence that contains just six amino acids-that is responsible for assembling the
MLL molecular switch in normal cells. The team members called this peptide
sequence the "Win" motif. They discovered that a synthetic version of this peptide
acts like a drug that breaks apart the MLL molecular switch, interrupting a critical
enzymatic process that is required to produce white blood cells. When used against
an MLL molecular switch that is broken-working too fast-the peptide drug
attacks the protein switch and breaks it apart, which may slow or stop the production
of the abnormal white blood cells. This drug may help to reprogram the way DNA is
packaged in leukemia cells and help convert the abnormal cells back into normal
cells.
"Reprogramming the way DNA is packaged in cancerous cells is a new idea that has
the potential to lead to better treatments with fewer side effects," Cosgrove says. "This
last year has been fantastic. We have been learning something new about these
proteins almost on a daily basis. Our hope is that as we continue to understand how
these DNA packaging proteins work, we will find new ways to treat all types of
leukemia as well as other diseases."
Cosgrove earned a Ph.D. at Syracuse University and was a postdoctoral researcher at
the Johns Hopkins School of Medicine and Cornell University. His research is funded
by a recent $100,000 New Investigator Award from the Leukemia Research
Foundation, the Basil O'Conner Award from the March Of Dimes Foundation, and
by a start-up grant from SU's College of Arts and Sciences. Further information
about his research is available at http://biology.syr.edu/cosgrove/COSGROVERESEARCH.HTML.
