In what is believed to be the largest genetic analysis of what triggers and propels progression of tumor growth in a common childhood blood cancer, researchers report that they have identified a possible new drug target for treating the disease.
T-cell acute lymphoblastic leukemia is one of the most common and aggressive childhood blood cancers. An estimated one-quarter of the 500 adolescents and young adults with this cancer diagnosis each year in the United States fail to achieve remission with standard chemotherapy drugs.
In Cell (2014; doi:10.1016/j.cell.2014.05.049), the researchers described how they used advanced genetic scanning techniques to identify 6,023 so-called long, noncoding strands of RNA that were active in the immune system T cells taken from 15 boys and girls with T-cell acute lymphoblastic leukemia, but not active in the healthy T cells in three young people without the disease.
Further analysis found that chemically blocking the action of one of those non-protein-producing RNAs stalled leukemia progression. The RNAs are known as leukemia-induced noncoding activator RNA-1, or LUNAR1 for short.
Study investigators say LUNAR1 was not singled out from RNA typically used by DNA to make proteins, but rather from among the most prevalent RNA, which are long chemical strands of translated DNA, previously termed junk DNA. These strands can help transcribe DNA but never fully assemble proteins. They say these long noncoding RNAs are increasingly recognized as key to regulating many cell functions.
The study offers preliminary evidence that drugs blocking LUNAR1 could treat T-cell acute lymphoblastic leukemia and a long-sought alternative to chemotherapeutic drugs that kill both cancer and normal cells, explained senior study investigator and NYU Langone cancer biologist Iannis Aifantis, PhD, in New York, New York. He added that LUNAR1 could aid in diagnosing the blood cancer.
“Our study shows that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia and plays a key role in how this cancer develops,” he said, pointing out that overproduction of LUNAR1 was recorded in almost all (90%) of leukemia patients tested.
Moreover, Aifantis said, his team’s latest findings suggest that development of future cancer therapies based on the underlying genetics of each patient should involve “not just mutations in someone’s DNA, but also alterations in the makeup of RNA.”
Among the study’s other key findings was that while LUNAR1 does not produce cancerous proteins on its own, its production was essential to the cell-to-cell signaling action of another protein, insulin-like growth factor 1 receptor (IGF-1R), already tied to many cancers, including leukemia.
Aifantis said that his team’s next steps are to develop more effective inhibitors of LUNAR1, preferably something that would precisely target any one or more of its 200-plus component nucleotides.