Johns Hopkins Kimmel Cancer Center scientists have
found a set of "master switches" that keep adult
blood-forming stem cells in their primitive state.
Unlocking the switches' code may one day enable scientists
to grow new blood cells for transplant into patients with
cancer and other bone marrow disorders.
The scientists located the control switches not at the
gene level but farther down the protein production line in
more recently discovered forms of ribonucleic acid, or RNA.
MicroRNA molecules, once thought to be cellular junk, are
now known to switch off activity of the larger RNA strands
that allow assembly of the proteins that let cells grow and
function.
"Stem cells are poised to make proteins essential for
maturing into blood cells, but microRNAs keep them locked
in their place," said cancer researcher Curt Civin, who led
the study. The journal account appeared online the week of
Feb. 5 in the early edition of the Proceedings of the
National Academy of Sciences.
To halt protein assembly, microRNAs pair up with
matching full-length RNA, then fold and twist it, rendering
the larger RNA useless. But the RNA pairings are not
perfect, and one microRNA can latch on to several hundred
RNA strands. "They act like a single circuit breaker to
efficiently control hundreds of RNAs," said Civin, the
Herman and Walter Samuelson Professor of Cancer Research in
the School of Medicine.
Robert Georgantas, research associate at the Kimmel
Cancer Center and first and corresponding author of the
study, said, "We're looking for ways to flip these microRNA
switches, to control when stem cells grow into new blood
cells."
To identify the key microRNAs, Georgantas sifted
through thousands of RNA pieces with a custom-built
computer software program. Its algorithms let the software,
fed data from samples of blood and bone marrow from healthy
donors, match RNA pairs. The outcome was a core set of 33
microRNAs that match with more than 1,200 of the larger
variety RNA already known to be important for stem-cell
maturation.
Georgantas and Civin currently are testing whether
these pair predictions are valid by using a nonreproducing
virus to insert genetic instructions for each of the 33
microRNAs into adult stem cells. The cells will then be
cultured in Petri dishes. MicroRNA-155 — the first
microRNA tested — was predicted to stop stem cells
from developing into red and white blood cells. As
expected, stem cells without microRNA-155 matured; they
formed approximately 75 red and 150 white blood cell
colonies per dish. Stem cells with microRNA-155 matured
into far fewer red and white cell colonies — about
seven and 30 per dish, respectively.
"Using microRNAs to stall an adult blood stem cell in
its early stage could help us grow new ones in test tubes,
and perhaps give us more insight into stem-cell maturation
for other tissue types," Civin said.
Civin and his team have filed for patents on the
microRNA technology. The research was funded by the
National Institutes of Health, National Cancer Institute,
National Foundation for Cancer Research and Kimmel
Foundation for Cancer Research.
Additional authors are Richard Hildreth, Sebastien
Morisot and Jonathan Alder, all of Johns Hopkins;
Chang-gong Liu, George A. Calin and Carlo Croce, of Ohio
State University; and Shelly Heimfeld, of the Fred
Hutchinson Cancer Research Center.
Johns Hopkins holds patents on the CD34 monoclonal
antibodies and inventions related to stem cells. Civin is
entitled to a share of the sales royalty received by the
university under licensing agreements between the
university, Becton Dickinson Corp. and Baxter HealthCare
Corp. The terms of this arrangement are being managed by
the university in accordance with its conflict-of-interest
policies.
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