Gene Sequencing Project Identifies Abnormal Gene Responsible for Rare Childhood Cancer
New research identifying a gene responsible for a rare and tough-to-cure subtype of childhood leukemia is laying the groundwork for clinical and treatment advances. Stephen D. Nimer, M.D., Director of Sylvester Comprehensive Cancer Center, was co-author of the study published November 13 in the journal Cancer Cell.
“My lab has been studying acute megakaryoblastic leukemia in adults for more than a decade,” Nimer said. “So when this wonderful opportunity came up to contribute to the efforts of a world class group of investigators, led by Tanya Gruber and James Downing, to intensively study the same type of leukemia in children, we jumped at the chance. Although childhood leukemia is often curable, this type of leukemia is often fatal. So the insights into what ‘drives’ this type of leukemia are not only scientifically important, but they will help us develop new therapeutic strategies.”
For the study, “An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia,” investigators performed transcriptome sequencing on diagnostic leukemia cells from 14 pediatric patients with acute megakaryoblastic leukemia (AMKL), which accounts for about 10 percent of pediatric acute myeloid leukemia cases. In seven of 14 cases, a cryptic inversion on chromosome 16 created a fusion gene – an alteration that directly contributes to leukemia.
AMKL patients with the fusion gene – which fuses the blood protein CBFA2T3 with GLIS2, a protein that is normally only produced in the kidney – also were found to be at high risk of failing therapy. Researchers found that only about 28 percent of AMKL patients with the fusion gene were long-term survivors, compared to 42 percent of patients without the fusion gene.
Additional sequencing of DNA from adult and pediatric AMKL patients found that the fusion protein was unique to pediatric cases. The gene GLIS2, which is responsible for turning other genes on or off, is normally switched off in the blood cells and has not previously been linked to cancer. However, researchers showed that GLIS2 and the CBFA2T3-GLIS2 fusion gene affected critical pathways that control cancel cell behavior. The affected genes, BMP2 and BMP4, will be the focus of additional research.
The study was part of the Pediatric Cancer Genome Project, a three-year collaboration between St. Jude Children’s Research Hospital and Washington University to sequence the complete normal and cancer genomes of 600 children and adolescents with some of the most aggressive and least understood cancers.