DS-ALL: An Ever-Changing Genetic Mutation Landscape

Children with Down syndrome are at an increased risk for developing leukemia – as much as 50 times more likely than other children. In a study recently published in Nature Communications, researchers seem to have identified genetic mutations that drive the development of acute lymphocytic leukemia in patients with Down syndrome (DS-ALL) – representing potential targets for treatment.

Led by Sergey Nikolaev, PhD, from University of Geneva Medical School, investigators analyzed the DNA sequences of 42 DS-ALL samples from 39 patients. They uncovered three genes that had the potential to mutate normal blood cells to cancer cells: RAS, CRLF2, and JAK2. Additionally, KRAS mutations occurred in 21 percent of DS-ALL sequences, and the majority of KRAS-mutated primary DS-ALL cases had poor outcomes – either death or relapse.

Of note, RAS mutations were almost completely mutually exclusive with JAK2 mutations, driving a combined total of two-thirds of analyzed cases. “RAS mutations in many cases seem to appear in later sub-clones, or in relapses, accompanied by the complete disappearance of JAK2 mutations,” the authors wrote.

While the link has been seen in other types of non-DS leukemia, the current pairing of RAS and JAK2 mutations is the most “clear-cut” evidence of the relationship so far, co-author Dean Nizetic, MD, PhD, from Queen Mary University in London and the Lee Kong Chian School of Medicine in Singapore, told ASH Clinical News.“In fact, fueled by our observation on DS-ALL, we re-analyzed recently published data on [DS-acute megakaryoblastic leukemia] and found that a complete mutual exclusion pattern is followed in that disease, too.”

Children with DS-ALL have worse survival outcomes and do not tolerate chemotherapy well, so there is a need for better, more targeted therapeutic regimens in this patient population, the authors explained. In light of the current findings, standard chemotherapy regimens for DS-ALL could be improved by patient stratification based on profiling these mutations, Dr. Nikolaev and co-authors concluded. More specifically, clinicians may consider adding KRAS inhibitors and/or chromatin modifier enzyme inhibitors to DS-ALL therapeutic strategies.

Commenting on the study’s findings, Edward Allan R. Sison, MD, assistant professor in the department of pediatrics at Texas Children’s Cancer and Hematology Centers in Houston, Texas, pointed out that various JAK and RAS inhibitors are currently in development and may prove efficacious in JAK2– or RAS-mutated DS-ALL.

“From a drug development perspective, these inhibitors would first be tested in patients with relapsed disease,” he added. “While targeted therapies are generally better tolerated than traditional cytotoxic chemotherapy, it is unlikely that JAK and/or RAS inhibitors would be used as a single agent, and would likely be used combined with salvage chemotherapy in a child who relapsed.”

Dr. Sison also noted that the type of next-generation sequencing employed in this study may not be available at all institutions, but the technology will prove valuable in future clinical trials as a way to “prospectively identify genetic alterations that may portend a poor prognosis” in these patients.

Nikolayev SI, Garieri M, Santoni F, et al. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nat Commun.2014 Aug 8;5:4654.