Master Regulatory Gene Found That Guides Fate
Of Blood-Producing Stem Cells
Discovery May Lead to New Therapies For Leukemia, Other Blood Disorders
(Philadelphia, PA) - Researchers from the University of Pennsylvania
School of Medicine found that a protein called NF-Ya activates
several genes known to regulate the development of hematopoietic stem
cells (HSC), or blood-producing stem cells, in bone marrow. Knowing the
details of this pathway may one day lead to new treatments for such blood
diseases as leukemia, as well as a better understanding of how HSCs work
in the context of bone-marrow and peripheral-stem-cell transplantation.
The authors published their findings in the early August issue of the
Proceedings of the National Academy of Sciences.
“Understanding the biology behind how the body precisely controls
stem-cell fate is one of the most important issues in stem-cell biology,”
says senior author Stephen G. Emerson, MD, PhD, Associate
Director of Clinical Research for Penn’s Abramson Cancer
Center and Chief of the Division of Hematology-Oncology. When
HSCs divide, they have one of three fates: develop into two more stem
cells, which is called self-renewal; differentiate to become one of several
mature blood-cell types; or strike a balance in which one daughter cell
becomes an HSC and the other becomes a mature blood-cell type.
“We know that in diseases like leukemia, the first scenario-no differentiated
cells, two HCSs developing-must occur because more and more stem cells
are made,” explains Emerson. In conditions like bone-marrow failure,
the second scenario-two differentiated cells and no HCSs-happens because
the body runs out of HSCs.
“We want to figure out how this process is normally regulated in
the body, so that we can learn to control it for therapeutic purposes,”
says Emerson. “For some clinical purposes, we might want to shift
the balance so that we can grow more stem cells, for those who need them.
Conversely, for patients in whom this process has gone awry, such as acute
leukemia, we might block the regulatory gene to shift the balance of self-renewal
versus differentiation so that all the immature, leukemic cells differentiate
Over the past 10 years, several gene families have been suggested to be
important in regulating HSC fate-for example homebox, wnt, notch 1, and
telomerase genes. Emerson and colleagues figured that one transcription
factor, called NF-Y, was required for activating promoters of all of these
genes. What’s more, they found that fully assembled NF-Y was activated
in stem cells and disappeared when the stem cells became mature cell types,
through the induction and loss of one its subunits, NF-Ya.
“When we overexpressed NF-Ya in stem cells, the stem cells produced
ten- to twenty-fold more stem cells after transplantation,” says
Emerson. “This makes NF-Ya the prime candidate for a master-regulatory
gene for multiple, if not all, stem-cell division programs.” NF-Ya
would be considered the master regulatory gene since it activates multiple
HSC regulatory genes and promotes HSC self-renewal.
Practically, the researchers’ goal is to find a way to control stem-cell
fate by biochemically turning NF-Ya on or off at will, to either make
more stem cells in the case of bone-marrow failure and for transplantation,
or to force the cells to differentiate, in the case of leukemia, where
too many HSCs are made.
Co-authors are Jiang Zhu, Yi Zhang, Gerard J. Joe, and Richard Pompetti,
all from Penn.
The Abramson Cancer Center of the University of Pennsylvania
was established in 1973 as a center of excellence in cancer research,
patient care, education and outreach. Today, the Abramson Cancer Center
ranks as one of the nation’s best in cancer care, according to U.S.
News & World Report, and is one of the top five in National Cancer
Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive
cancer centers in the United States. Home to one of the largest clinical
and research programs in the world, the Abramson Cancer Center of the
University of Pennsylvania has 275 active cancer researchers and 250 Penn
physicians involved in cancer prevention, diagnosis and treatment.
PENN Medicine is a $2.7 billion enterprise dedicated
to the related missions of medical education, biomedical research, and
high-quality patient care. PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in 1765 as the nation's first
medical school) and the University of Pennsylvania Health System.
Penn’s School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #4 in the nation in U.S. News &
World Report’s most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students, the School
of Medicine is recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders of academic
The University of Pennsylvania Health System includes: its flagship hospital,
the Hospital of the University of Pennsylvania, consistently rated one
of the nation’s “Honor Roll” hospitals by U.S. News
& World Report; Pennsylvania Hospital, the nation's first hospital;
Penn Presbyterian Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities; and home health
care and hospice.