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Key player found for a cancer typical in Down syndrome
Date:3/1/2010

). The increased incidence of this leukemia in children with Down syndrome convinced the researchers that a GATA1 mutation may be joining forces with some genetic factor on chromosome 21 specifically, miR-125b-2.

"GATA1 is always mutated, while miR-125b-2 is always over-expressed in leukemic cells," Li says. "Do they cooperate?"

The researchers experimented on genetically engineered mice that specifically expressed the mutant version of GATA1. Cells were taken from the fetal livers of these mice and induced into becoming blood progenitor cells that either made both red blood cells and megakaryocytes (MEP) or only made megakaryocytes (MP). The researchers then used a virus to over-express miR-125b-2 in these cells and compared them to MEP and MP cells without a GATA1 mutation.

Although over-expression of miR-125b-2 caused increased growth and replication of MEP and MP cells with or without the GATA1 mutation, the growth was further enhanced in the presence of the GATA1 mutation. But once the researchers down-regulated this microRNA in DS-AMKL leukemic cells, which have both GATA1 mutation and miR-125b-2 over-expression, the aberrant growth stopped. These observations support the notion that GATA1 mutation and over-expression of miR-125b-2 are both needed for DS-AMKL to develop.

Further tests on these cells suggested that over-expression of miR-125b-2 spurs the leukemia by silencing two genes: one for tumor-suppression, and another for producing other regulatory microRNAs.

Genetic analyses of leukemia cells taken from DS-AMKL patients confirmed the results seen in the mouse models. The next step is for researchers to model DS-AMKL in vivo, using animal cells and, eventually, fetal cells.

Studying leukemia in Down syndrome patients may help scientists understand and treat other forms of the cancer, says Orkin. Past research has shown that other genes on chromosome 21 may be involved in other types of leukemia. "Le
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Contact: Rob Graham
617-919-3110
Children's Hospital Boston
Source:Eurekalert

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