Subclone Mutation May Cause Relapse in Acute Lymphoblastic Leukemia Patients

For the first time, researchers believe they know how malignant cells evolve and cause relapse in acute lymphoblastic leukemia (ALL) patients.

For the first time, researchers believe they know how malignant cells evolve and cause relapse in acute lymphoblastic leukemia (ALL) patients. Researchers at St. Jude Children’s Research Hospital are reporting they have new insights into the genetic basis of treatment failure in ALL patients. The findings may have implications for the early detection of mutations driving relapse.

In a study published in the March 19, 2015 issue of the journal Nature Communications, they report on the use of deep, whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric acute lymphoblastic leukemia patients from diagnosis to relapse. They found that clonal diversity is comparable at diagnosis and relapse. In addition, the researchers report that clonal survival from diagnosis to relapse is not associated with mutation burden. The study identified six pathways that were frequently mutated, and there were seven mutations found to be enriched at relapse: NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.

The researchers report that 50% of the leukemia cells had multiple subclonal mutations in a pathway or gene at the time of diagnosis. However, there was generally only one "minor clone" that survived therapy.  This minor clone acquired additional mutations and became the relapse founder clone. In nine of the cases, the researchers discovered that the relapse-specific mutations were in NT5C2, with mutations in four cases being in descendants of the relapse founder clone.

Study investigator Jinghui Zhang, PhD, who is a member of the St. Jude Department of Computational Biology, said new genomic analytical technologies enabled the scientists to detect with great sensitivity the mutations in both the "rising" and "falling" clones at the different stages. Dr. Zhang said that a majority of scientists had thought the clone that had the most mutations is more likely to survive therapy and evolve.  However, that doesn’t seem to be the case. A key finding was that in most cases, relapse of the cancer was driven by a subclone present at an extremely low level.  She said these genomic findings may lead to new tests to monitor patients in remission and to detect signs of relapse.

Dr. Zhang said when clinicians are analyzing the level of minimum residual disease while monitoring patients in remission; they should not only pay attention to the mutations in the predominant clone, but also the kinds of mutations that exist in the minor subclones. Researchers at St. Jude and elsewhere are currently exploring the biological functions of the relapse-related genes, and the results may aid in developing ways to identify drugs to target their function.  

Dr. Zhang said the methodology of highly sensitive genomic analysis of cancer cells that she and her colleagues developed can be applied to explore the evolution of other cancers as well.