A new drug target for treating leukemia has been identified as part of the largest ever genetic analysis of tumor growth in childhood blood cancer. T-cell acute lymphoblastic leukemia is one of the most common and aggressive childhood blood cancers. Every year, an estimated 500 american youths with this blood cancer fail to achieve remission through standard chemotherapy. With genetic scanning techniques, researchers at NYU Langone Medical Center identified 6,023 long, non-coding strands of RNA active in immune system T cells taken from a group of T-cell acute lymphoblastic leukemia patients. These strands of RNA from the 15 patients were not active in the healthy T cells of three young people who didn’t have leukemia.
Publishing their findings in the journal Cell, researchers describe how they were able to block the action of one of these RNA strands, leukemia-induced non-coding activator RNA-1 or “LUNAR1”, which slowed leukemia progression. Long-coding sequences of RNA, such as LUNAR1, are more frequently being recognized as important in regulating cell functions. Beforehand, they were more though of as “junk DNA”, which help transcribe DNA without fully assembling proteins. Although LUNAR1 does not produce cancerous proteins itself, it forms an important part of the signaling action of a protein related to many cancers.
The researchers discovered LUNAR1 through examining RNAs active in a biological pathway known as NOTCH1. This pathway is active in at least half of all T-cell actue lymphoblastic leukemia patients, and the researchers discovered that LUNAR1 was the most highly expressed long, non-coding RNA associated with NOTCH1. Among normal T cells, NOTCH1 is inactive, and LUNAR1 and another long, non-coding RNAs are not transcribed and can’t bind to an activate IGF-1R. They found that LUNAR1 was overproduced in 90% of the leukemia patients in the study. Drugs that block LUNAR1 could therefore form the basis of an alternative treatment to chemotherapy, which kills both healthy cells and cancer cells.
The study reveals that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia, and plays a key role in how this cancer develops. To test this hypothesis, the scientists transplanted human leukemia T cells into mice and then successfully stalled tumor growth in a subset of the mice by chemically blocking LUNAR1. This research suggests that future therapies for cancer should take into account the RNA make-up of individual patients, as well as mutations in their DNA. The team now needs to develop drugs that will more effectively inhibit LUNAR1, perhaps through targeting its component nucleotides.