August 1, 2005
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 and die.
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,
“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.
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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,
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