Researchers who have studied the activity of thousands of genes in a drug-resistant form of childhood leukemia are now proposing that the disease be called mixed-lineage leukemia (MLL) because it is a distinct disease, and not a subtype of the more prevalent acute lymphoblastic leukemia (ALL).
Howard Hughes Medical Institute investigator Stanley J. Korsmeyer and colleague Todd Golub led the research team, both work at the Dana-Farber Cancer Institute at Harvard Medical School. The team theorised that the MLL translocation might cause aberrations in metabolic pathways that would indicate that the drug-resistant form of leukemia they were studying was genetically different from ALL, and thus a distinct form of leukemia.
They decided to use DNA microarrays to test their hypothesis by comparing the expression of genes in the lymphocytes of children with classic ALL versus lymphocytes from children with the chromosome 11 translocation. DNA microarrays, popularly known as gene chips, are large collections of genes that are arrayed on a postage-stamp-sized chip. To study gene activity in cells, researchers extract collections of RNA from cells and apply those collections to the microarray. By measuring the level of fluorescence of markers attached to the RNA, the researchers are able to determine the level of gene activity, or expression, of each gene.
In their studies, the scientists compared the gene expression profiles of MLL and ALL cells using a commercial DNA microarray containing more than 12,000 genes. They discovered that about 1,000 genes were under-expressed in MLL compared to ALL, and about 200 genes were expressed at higher levels.
The researchers concluded that the gene expression profiles "show that ALLs possessing a rearranged MLL have a highly uniform and distinct pattern that clearly distinguishes them from conventional ALL or acute myelogenous leukemia and warrant designation as the distinct leukemia, MLL."
The research also uncovered promising drug targets that may improve treatment of MLL, said Korsmeyer. Specifically, he cited as an example a gene called FLT3, whose increased activity most clearly distinguished MLL from ALL or AML. The FLT3 gene encodes an enzyme that is a cellular switch called a tyrosine kinase, a type of enzyme that is already targeted by drugs that are in development.
For further information go to the Howard Hughes Medical Institute.
