Protein Loss Plays Role in Acute T-cell Leukemia
The loss of a key protein (Smad3) in a pathway that helps prevent
tumors from forming is specific to one form of childhood leukemia,
but not to other pediatric and adult forms of leukemia, according
to a new study published in the August 5, 2004, New England Journal
of Medicine*. The study was done by scientists at the National
Cancer Institute (NCI), part of the National Institutes of Health
(NIH), and gives researchers new insights into how leukemias vary
on a molecular level.
Smad3 is an important player in a cellular network relay system
called the transforming growth factor Β (TGF-Β) signaling
cascade. TGF-Β binds to receptors on the surface of blood cells that
develop in bone marrow and activates a multi-protein cascade that
relays these external signals into the nucleus of the cell. These
signals typically slow the rate at which these blood cells proliferate.
Thus, when this signal pathway is interrupted, TGF-Β can no longer
control cell proliferation, and this potentially can lead to leukemia
a cancer of blood cells.
To better understand the role of Smad3 in this pathway and how
it may vary in different forms of leukemia, John Letterio, M.D.,
and a team of researchers looked for the presence of Smad3 protein
in samples of human leukemia cells collected from patients with
one of three different childhood leukemias: a T-cell derived leukemia,
B-cell derived leukemia (both are a type of white blood cell known
as a lymphocyte), and non-lymphocyte leukemia. Smad3 protein was
present in the B-cell and non-lymphocyte samples, but almost non-existent
in all the T-cell samples. This lack of Smad3 protein also appears
to be restricted to childhood T-cell leukemia, because the researchers
demonstrated that Smad3 was present in two adult forms of T-cell
leukemia: Sezary syndrome and a virus-induced (HTLV-1) leukemia.
In mice, deletion of one or both copies of the Smad3 gene specifically
impairs the ability of TGF-Β to stop T-cell proliferation, so the
discovery that Smad3 was unique to the T-cell leukemia was not surprising.
The surprise and mystery of these findings is the biology behind
Smad3's absence. The leukemia cells produced normal levels of Smad3
mRNA the instructions that cells use to make protein indicating
that the Smad3 gene is turned on. Furthermore, the researchers found
that the sequence of the Smad3 gene in patient samples was identical
to the normal Smad3 gene found in healthy T cells, signifying that
a genetic mutation was not the culprit either.
"We don't yet know the mechanisms behind this loss of Smad3
protein," said Letterio, "but two possibilities may be
that protein synthesis is being blocked or that the protein is made
but degraded very quickly."
What the researchers do know is that Smad3 loss alone is likely
not responsible for onset of leukemia, since the Smad3-deficient
mice do not develop tumors despite their increased number of T-cells.
To address this idea that some other factor is required, Letterio's
group examined the connection between Smad3 and p27Kip1, another
protein with an important role in regulating cell growth. Mice with
p27Kip1 deleted have increased numbers of T-cells but, similar to
mice with Smad3 deleted, they do not develop leukemia. However,
when the researchers deleted one copy of the Smad3 gene in these
p27Kip1-deficient mice, 50 percent of the mice died within six months,
and several of them developed leukemia. Mice with both p27Kip1 and
Smad3 completely deleted could not be studied, as most died as embryos.
The researchers hope that continued work will uncover other genetic
alterations that, when linked with Smad3 loss, play a role in the
genesis of pediatric T-cell leukemia. Letterio also pointed out
that their study did not examine all the variations of leukemia.
"Whether or not Smad3 plays a role in other forms of leukemia
is still an open question," he said.
For more information about cancer, visit the NCI Web site at http://www.cancer.gov
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
*Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole
DE, Byfield S, Felici A, Flanders KC, Walz TM, Roberts AB, Aplan
PD, Balis FM, and Letterio JJ. "Loss of Smad3 in Acute T-Cell
Lymphoblastic Leukemia", New England Journal of Medicine, Vol