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DURHAM, N.C. -- Scientists at the Duke Comprehensive Cancer
Center have identified a critical switch that turns on a
blood stem cell's prized ability to regenerate itself while
also producing a variety of daughter cells. These daughter
cells are capable of becoming mature blood and immune system
cells.

The switch is a protein called Notch that resides on the
surface of stem cells. When Notch activity is turned off, stem
cells quickly lose their potency and begin to change into more
mature cells that can no longer produce new blood-forming
cells.

Their findings are published in the March, 2005 issue of
Nature Immunology, to be published on-line January 23,
2005.

"We're excited about these results because they help explain
the basic mechanism by which stem cells regenerate," said
Tannishtha Reya, Ph.D., assistant professor of Pharmacology and
Cancer Biology at Duke. "Our findings may also open the door to
more successful manipulation of stem cell growth for treatment
of a variety of diseases."

Previous research had suggested that activation of Notch --
a protein known to be crucial to the development of embryos in
virtually all animals from flies to humans -- could also
influence growth of blood-forming cells. But whether or not it
was required for proper development of blood forming stem cells
and its exact role in this context was unknown, said Reya.

Reya, graduate student Andrew Duncan, postdoctoral fellow
Frederique Rattis and their colleagues answered this question
by studying mice developed by Nicholas Gaiano, a collaborator
from Johns Hopkins University. These mice contain an engineered
gene sequence capable of producing a fluorescent signal when
Notch signaling is activated.

The fluorescent protein allowed them to track where Notch
was active during blood cell development and to see when it had
been turned off. The studies revealed strong signals in the
portion of bone marrow where the potent "hematopoietic" or
blood-forming stem cells reside. The levels of Notch signal
decreased rapidly as these stem cells committed to becoming
fully mature cells.

Moreover, when the researchers selectively inactivated the
Notch gene, the stem cells could not maintain themselves and
quickly began to change into more mature cells.

"When we inhibited Notch activity in stem cells, they
rapidly committed and differentiated into mature lineages,"
said Reya. "That finding, together with the data showing Notch
function is shut off physiologically as cells commit to
specific lineages, suggests that turning off Notch is a
mechanism that allows stem cells to become sensitive to
differentiation cues. Thus, Notch appears to act as a switch
that can influence the balance between self-renewal and
commitment."

The results also helped clarify the role of another stem
cell signal called Wnt, which Reya and her colleagues showed in
previous studies is also necessary for normal stem cell
survival and proliferation. Reya said the two signals – Notch
and Wnt -- likely have distinct roles in self-renewal or
regeneration.

"Our current work suggests that, at least in hematopoietic
stem cells, Notch may have a dominant role in maintaining stem
cells in an undifferentiated state while Wnt may have a
dominant role in proliferation and survival."

Understanding the signals that both maintain stem cells in
their undifferentiated state and allow them to proliferate
could enable a patient's or donor's hematopoietic stem cells to
be grown in the laboratory, providing an enriched source of
stem cells for transplantation. The findings may also help
explain why aberrant Notch signaling leads to T cell leukemias
and other cancers, said Reya.

In blood cancers such as leukemias and lymphomas, the blood
cells fail to mature and they multiply abnormally. Physicians
have successfully treated acute promyelocytic leukemia (APL)
using a drug called retinoic acid, which forces the cancerous
cells to mature or differentiate. Forcing the cells to mature
also stops excessive proliferation and restores the natural
cycles of cell death, effectively stopping the cancerous
process.

"If Notch promotes leukemia by locking cells in an
undifferentiated state, then inhibiting Notch would force
leukemic cells to differentiate and could potentially be used
as a therapy." Reya said.

The research team also included Leah DiMascio, Kendra
Congdon, Gregory Pazianos, Chen Zhao, J. Michael Cook and Karl
Willert of Duke and Keejung Yoon and Nicholas Gaiano of Johns
Hopkins University School of Medicine. The research was funded
by American Heart Association predoctoral fellowships (A.W.D.
and K.L.C.), Burroughs Wellcome Fund career award (N.G.),
Kimmel Foundation scholar award (N.G.), Cancer Research
Institute investigator award (T.R.), Ellison Medical Foundation
Scholar Award (T.R.) and the National Institutes of Health
(T.R.).