Genetic Alterations Predict Treatment Success in High-Risk Pediatric Leukemia

Several genetic alterations help identify which high-risk pediatric patients with acute megakaryoblastic leukemia (AMKL) need allogeneic stem cell transplants.

When genes are broken and reassemble, fusion genes develop. These genes can lead to abnormal proteins that drive unchecked cell division and other cancer hallmarks.

In a study published in Nature Genetics, investigators found that fusion genes CBFA2T3-GLIS2, KMT2A and NUP98-KDM5A, are associated with reduced survival compared with other pediatric AMKL subtypes.

The study is the largest to-date that used next-generation sequencing technology to define genetic missteps that drive AMKL in children without Down syndrome. The genetic basis of AMKL has been previously identified in children with Down syndrome, however, the cause was unknown in 30% to 40% of other pediatric cases.

“Because long-term survival for pediatric AMKL patients without Down syndrome is poor, just 14% to 34%, the standard recommendation by many pediatric oncologists has been to treat all patients with allogeneic stem cell transplantation during their first remission,” said senior and co-correspond author Tanja Gruber, MD, PhD. “In this study, we identified several genetic alterations that are important predictors of treatment success. All newly identified pediatric AMKL patients without Down syndrome should be screened for these prognostic indicators at diagnosis. The results will help identify which patients need allogeneic stem cell transplants during their first remission and which do not.”

The authors also recommend that AMKL patients be tested for mutations in the GATA1 gene, a hallmark of AMKL in children with Down syndrome, who almost always survive their disease.

The results of the study showed that AMKL patients with GATA1 mutations and no fusion genes, have the same successful outcome.

“The results raise the possibility that pediatric AMKL patients without Down syndrome who have mutations in GATA1 may benefit from the same reduced chemotherapy used to treat the leukemia in patients with Down syndrome,” Gruber said.

The revised recommendations for diagnostic screening and treatment of AMKL are currently being implemented at St. Jude, the authors noted.

The investigators used next-generation sequencing of the exome or RNA of 89 pediatric AMKL patients with Down syndrome, who were treated at collaborating institutions in the United States, Europe, and Asia.

In addition to the sequencing data, the investigators analyzed the patient’s gene expression and long-term survival. The results of the study showed that non-Down syndrome pediatric patients with AMKL could be divided into 7 subgroups—–including the newly identified HOX subgroup––based on underlying genetic alteration, treatment outcome, and pattern of gene expression.

Of the 89 study participants, 15% were in the HOX subgroup, characterized by different HOX fusion genes. HOX alterations have been reported in other types of leukemia, according to the authors.

Cooperating mutations that fuel AMKL indifferent subgroups were also identified, including changes in the RB1 gene and recurring mutations in the RAS and JAK pathways in cells. The alterations have been reported in other cancers.