Landmark Study Creates Acute Lymphoblastic Leukemia Mutation Roadmap

Scientists from St. Jude Children’s Research Hospital have created a roadmap of the genetic mutations present in the most common childhood cancer, acute lymphoblastic leukemia (ALL). 

Understanding the impact of genetic differences on cancer outcomes allows physicians to sequence patients’ cancer and personalize treatments. For this reason, the findings—published recently in Nature Genetics—create a foundational guide for physicians and scientists to understand disease development and improve treatment outcomes.  

Most children with ALL will survive, but a fraction do not respond well to therapy. The St. Jude team found that in leukemia that is normally considered low risk, a single specific genetic rearrangement was associated with a significantly increased risk of relapse.

“In this study, we were able to comprehensively define the number and type of recurrently altered genes that are found in childhood ALL,” says author Charles Mullighan, Ph.D., M.B.B.S., St. Jude Department of Pathology. “Because of the scale of the study, we could identify many newly implicated genes that have not been reported in leukemia or cancer at all, and to show that they fall into several new cellular pathways.”

The research was unique because it included 2,574 pediatric ALL patient samples, the largest such cohort ever published. Earlier studies have typically studied hundreds of samples, or fewer. St. Jude investigators collaborated with the Children’s Oncology Group to collect samples over more than a decade.  The samples were subjected to a combination of whole genome, whole exome, or transcriptome sequencing. The researchers compared the sequences to find patterns in the mutations. These patterns can serve as roadmaps to understand how the cancer develops and how it may respond to treatment.

“The study demonstrates the power of the data,” says co-author Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology. “If you don't have a sufficient number of patient samples, you lack the statistical power to find drivers present at a low prevalence. Once we had the power, we found a subgroup of new drivers involved in ALL development.” The new drivers included a type of protein modification, “which was really exciting, because we have never anticipated in the past that this group of proteins will be involved in disease initiation for leukemia,” she adds.

On average, the pediatric cancer samples had four mutations that drove development of ALL.  The work identified 376 significantly mutated genes that potentially drive cancer development, 70 which have never been implicated in ALL. Some of the unexpected potential driver mutations are in genes involved with cellular processes such as ubiquitination, SUMOylation or non-coding cis-regulatory regions.

The researchers also found differences in the mutations present in subtypes of ALL, which may affect clinical care. For example, two of these groups involved specific genetic rearrangements that differed by CEBPA/FLT3 or NFATC4 gene expression. This observation may have clinical implications, as new FLT3 inhibitors are in clinical trials, suggesting the CEBPA/FLT3 ALL subtypes may be sensitive to such therapies, but the other subgroup may not be.

The researchers’ work revealed the sequence of mutation events in many ALL cases, with potential implications for treatment. In hyperdiploid B-cell ALL (B-ALL), cancer cells have at least five more chromosomes than normal (46 in humans). A long-standing question has been the relative timing of chromosomal gains, and other mutations, in the development of hyperdiploid ALL. Understanding this process would provide important insights into how leukemia develops.

The researchers traced the order of events leading to hyperdiploid ALL using computational modeling of the sequence of mutations and chromosomal gain data. This showed that in most hyperdiploid B-ALL cases, the chromosomal gains appear to happen early and all at once, a chromosomal “big bang.” Then, the precancerous cells gain more mutations, in part due to ultraviolet (UV) light induced DNA damage. The finding shows UV damage contributes to the development of ALL, a previously controversial notion.

Other scientists can access the data from the paper on the St. Jude Cloud, within the pediatric cancer data portal (PeCan) database.