UCLA scientists have shown that two common tumor suppressor genes, TSC and PTEN,
are vital to regulating the stem cell-like precursor cells that create the blood
supply in Drosophila, the common fruit fly.
The researchers examined a signaling pathway called TOR that the cells use to
gauge nutrition levels and stress, said study senior author Dr. Julian A.
Martinez-Agosto, an assistant professor of human genetics and pediatrics and a
researcher with UCLA’s Jonsson Comprehensive Cancer Center.
“We wondered how an organism knows how many blood cells to make and when to
make them in the context of injury and repair to tissue. In particular, we
wondered how the blood progenitor cells sense that change and know when it’s
time to make more blood cells,” said Martinez-Agosto, who also is a researcher
with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell
Research at UCLA. “We found that the TOR pathway uses these two genes to
regulate its function and, when activated, it expands or increases the number of
blood progenitor cells in the fly’s blood.”
The study appears Sept. 5, 2012 in the advance online issue of the
peer-reviewed journal Development.
Michelle Dragojlovic-Munther, a graduate student in the Martinez-Agosto
laboratory and first author of the study, found that cells with increased
activity of TOR have a competitive advantage, allowing them to divide and make
more of themselves so they can make blood. These progenitors,
Dragojlovic-Munther found, also have high levels of reactive oxygen species
(ROS)—ions or very small molecules that include free radicals—which are known to
damage cells and can predispose humans to aging and heart disease. But in this
case, the ROS proved valuable.
The precursors, Martinez-Agosto said, were producing ROS all the time and
when TOR was activated, the levels increased dramatically. Too much ROS caused
them to divide more than normal. If they treated the flies with antioxidants,
which reduce ROS levels, the cells would develop normally.
The finding could be important because the TOR pathway is abnormally
activated in many cancers, and it may be possible to target the levels of ROS,
which may help regulate the pathway.
“What this study may be telling us is that too much ROS is causing more cells
to divide and we may be able to target therapies that reduce ROS to
significantly improve the condition,” Martinez-Agosto said, adding that
specifically targeted antioxidants might be a potential treatment in certain
subsets of blood disorders. “Sometimes that pathway is working more than it
should, and we need the right amount of ROS for balance. It’s like Goldilocks,
there can’t be too little or too much. We need it just right.”
Going
forward, Martinez-Agosto and his team will try to determine where the ROS is
coming from and perhaps discover an enzyme that may be a good target for
therapeutics. They know that the higher ROS levels in blood progenitors are not
coming from mitochondria, the cell’s power source, but have not identified how
they are being produced.
“This study highlights mechanistic differences between TSC and PTEN on TOR
function and demonstrates the multifaceted roles of a nutrient-sensing pathway
in orchestrating proliferation and differentiation of myeloid-specific blood
progenitors through regulation of ROS levels and the resulting
myeloproliferative disorder when deregulated,” the study states.
The study was funded by a Ruth L. Kirschstein National Research Service Award
from the National Institutes of Health (GM007185) and the David Geffen School of
Medicine at UCLA.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and
clinicians engaged in disease research, prevention, detection, control,
treatment and education. One of the nation's largest comprehensive cancer
centers, the Jonsson center is dedicated to promoting research and translating
basic science into leading-edge clinical studies. In July 2012, the Jonsson
Cancer Center was named among the top 10 cancer centers nationwide by U.S. News
& World Report, a ranking it has held for 12 of the last 13 years. For more
information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.