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-beta (TGF-B ) signaling cascade. TGF-B 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-B 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-B 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.