A fusion gene that is responsible for 30% of a rare subtype of childhood leukemia with an extremely poor prognosis has been identified. This finding offers the first evidence of a mistake that gives rise to a significant percentage of acute megakaryoblastic leukemia (AMKL) cases in children.

AMKL accounts for about 10% of pediatric acute myeloid leukemia (AML). The discovery of the gene paves the way for desperately needed treatment advances.

Investigators traced the genetic misstep to the rearrangement of chromosome 16, which brings together pieces of two genes and sets the stage for production of an abnormal protein. The fusion protein has the front end of CBFA2T3, a blood protein, and the back of GLIS2, a protein that is normally produced only in the kidney. Using a variety of laboratory models, the research team found that the CBFA2T3-GLIS2 protein switched on genes that drive immature blood cells to keep dividing long after normal cells had died. This alteration directly contributes to leukemia.

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AMKL patients who had the fusion gene were found to be at high risk of failing therapy. When the long-term survival of 40 AMKL patients who were treated at multiple medical centers around the world was checked, about 28% of the patients with the fusion gene became long-term survivors, which was lower than the 42% for patients without CBFA2T3-GLIS2. The overall long-term survival for pediatric AML patients in the United States is now 71%.

“The discovery of the CBFA2T3-GLIS2 fusion gene in a subset of patients with AMKL paves the way for improved diagnostic testing, better risk stratification to help guide treatment and more effective therapeutic interventions for this aggressive childhood cancer,” said corresponding author James Downing, MD, scientific director at St. Jude Children’s Research Hospital. 

“We identified this unusual gene fusion by comparing the genome of children’s healthy cells with the genome of their cancer cells. This type of in-depth exploration and analysis is crucial to finding unexpected structural rearrangements in the DNA that can lead to cancer. With this discovery, we now can search for more effective treatment options that target this precise defect,” explained co-author Richard Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis, Missouri.

The study is part of the Pediatric Cancer Genome Project, a 3-year collaboration between St. Jude 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.

“We focused on AMKL because no one had any idea of what caused this leukemia in most patients,” said Tanja Gruber, MD, PhD, of the St. Jude Department of Oncology. The study excluded AMKL patients who were infants or children with Down syndrome because earlier research had linked their disease to other chromosomal rearrangements.

“Whole genome sequencing has allowed us to detect alterations in cancer cells that were previously unknown. Many of these changes contribute directly to the development of cancer,” Gruber said. “Such sequencing also provides the deeper understanding of the disease that is critical for developing more effective, less-toxic targeted therapies.”

This research was published in Cancer Cell (2012; doi:10.1016/j.ccr.2012.10.007).