The loss of a key protein (Smad3) in a pathway that helps prevent tumours from forming is specific to one form of childhood leukaemia, but not to other paediatric and adult forms of leukaemia, according to a new study done by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and gives researchers new insights into how leukaemia vary on a molecular level.

Smad3 is an important player in a cellular network relay system called the transforming growth factor B (TGF-B) signalling 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 leukaemia -a cancer of blood cells.

To better understand the role of Smad3 in this pathway and how it may vary in different forms of leukaemia, John Letterio and a team of researchers looked for the presence of Smad3 protein in samples of human leukaemia cells collected from patients with one of three different childhood leukaemias: a T-cell derived leukaemia, B-cell derived leukaemia (both are a type of white blood cell known as a lymphocyte), and non-lymphocyte leukaemia.

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 leukaemia, because the researchers demonstrated that Smad3 was present in two adult forms of T-cell leukaemia: Sezary syndrome and a virus-induced (HTLV-1) leukaemia.

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 leukaemia was not surprising. The surprise - and mystery - of these findings is the biology behind Smad3's absence. The leukaemia cells produced normal levels of Smad3 mRNA - the instructions that cells use to make protein -indicating that the Smad3 gene is turned on, the release from NIH says.

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," Letterio said adding, "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 leukaemia, since the Smad3-deficient mice do not develop tumours 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 leukaemia.

However, when the researchers deleted one copy of the Smad3 gene in these p27Kip1-deficient mice, 50 per cent of the mice died within six months, and several of them developed leukaemia. 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 paediatric T-cell leukaemia. Letterio also pointed out that their study did not examine all the variations of leukaemia. "Whether or not Smad3 plays a role in other forms of leukaemia is still an open question," he said.