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Monday, November 21, 2022

The Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia

By Dibash Kumar Das, PhD

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and most children with ALL will survive. Unfortunately, a small percentage of these patients do not respond well to therapy and relapse. Studies have shown that a better understanding of the differences in these patients' cancer genetics before starting treatment can help personalize treatments to individual patients and improve the likelihood of responding to different anti-cancer therapies (Haematologica 2020; https://doi.org/10.3324/haematol.2020.247031). 

A recent study demonstrated that a previously overlooked mutation was enough to significantly increase the risk of relapse in a subtype of pediatric leukemia that is normally considered low risk (Blood Cancer Discov 2022; doi: 10.1158/2643-3230.BCD-21-0160). Now, researchers have created a comprehensive “roadmap" of the genetic mutations that drive development across the landscape of diverse disease subtypes of ALL present at diagnosis. The landmark study from St. Jude Children's Research Hospital was published in the journal Nature Genetics (2022; https://doi.org/10.1038/s41588-022-01159-z).

Study Details
In the new work, St. Jude investigators collaborated with the Children's Oncology Group for more than a decade to collect samples from 2,574 pediatric patients with ALL. This created the largest cohort of its type to be published; in comparison, earlier studies collected only a few hundred samples or sometimes even fewer.

The collected samples were subjected to a combination of next-generation sequencing techniques such as whole-genome, whole-exome, or transcriptome sequencing. The group analyzed the sequences to find patterns in the mutations and identify new driver mutations of ALL. The findings revealed that, despite a generally low mutation burden, the pediatric cancer samples had an average of four putative somatic mutations that drove development of ALL. In total, 376 significantly mutated driver genes were identified varying in prevalence across ALL subtypes. Of these, 70 had never been linked to ALL.

Some of the unexpected potential driver mutations discovered are in genes associated with cellular processes, such as ubiquitination, SUMOylation, or non-coding cis-regulatory regions. The investigators also found differences in the mutations present in subtypes of ALL with potential clinical implications. For example, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups, suggesting that the CEBPA/FLT3 ALL subtypes may be sensitive to FLT3 inhibitor therapies, but the other subgroup may not be.

Furthermore, using computational modeling, the group revealed the sequence of mutation events that occur in many cases of ALL. In hyperdiploid B-cell ALL, which has at least five more chromosomes than normal), chromosomal gains are acquired early and synchronously. Then, the precancerous cells gain more mutations through damage caused by ultraviolet radiation. Other scientists can access the data from the paper on the St. Jude Cloud within the pediatric cancer data portal (PeCan) database.

Oncology Times reached out to corresponding author Charles Mullighan, MBBS (Hons), MSc, MD, for additional insights into their study. He is Deputy Director of the Comprehensive Cancer Center, Co-Leader of the Hematological Malignancies Program, and Medical Director of the St. Jude Biorepository at St. Jude Children's Research Hospital.

Oncology Times: Genomics of pediatric ALL has been studied for many years, yet relapsed ALL remains a major cause of cancer-related death. What are factors associated with a significantly increased risk of relapse?
Mullighan: “ALL is comprised of over 30 subtypes that have distinct initiating, somatic driver alterations, as well as cooperating genomic alterations. Both of these factors—the primary genomic subtype and associated genomic alterations—influence the risk of relapse. Many of these genetic features have only been identified by large-scale genomic studies in the last few years, and subsequent studies have shown that these are indeed strongly associated with relapse risk.
“Genomic evolution is also associated with relapse. There are several genomic alterations enriched or acquired after treatment begins that facilitate resistance to specific drugs. And [there's] some evidence that, conversely, specific drugs may promote the acquisition of mutations that drive resistance and relapse. We are also beginning to understand the genetic changes that promote resistance to newer immunotherapeutic agents. This study was not designed to provide a comprehensive overview of genetic associations with relapse, but rather a detailed landscape of genomic alterations present at diagnosis. However, the size of the study enabled identification of multiple previously unrecognized associations with relapse."
 
Oncology Times: This study discovered new driver mutations involved in ALL development. Are there any you find particularly noteworthy?
Mullighan: “Unexpected findings were the identification of new recurrently mutated pathways, particularly those involving RNA handling and protein modification (e.g., ubiquitination and SUMOylation). Functional studies are needed to determine the mechanistic effects of these alterations, but several in silico observations, such as mutual exclusivity of mutations of genes within a pathway and associations with specific subtype, suggest that these alterations have direct roles in leukemia formation."

Oncology Times: In terms of leukemia development, can you elaborate on the chromosomal "Big Bang"?
Mullighan: “This terminology was used to denote that, in the context of high hyperdiploidy in which leukemic cells exhibit gains of copies of multiple chromosomes, we were able to leverage the massive data available to show that, in the majority of cases, the chromosomal gains were acquired together rather than sequentially. This suggests there was a single catastrophic event leading to the chromosomal gains."
 
Oncology Times: How can the findings of this study help refine the treatment strategies of pediatric acute lymphoblastic leukemia?
Mullighan: “Several observations are of clinical interest. First, we showed that many of the more recently described genomic subtypes are associated with risk of relapse. Thus, precise identification of these subtypes at the time of diagnosis using genomic technologies is important. That is already the approach used at St. Jude Children's Research Hospital, where all children diagnosed with cancer are offered the option of clinical whole genome and transcriptome sequencing.
“A second observation was that the study identified genomic markers that predicted outcome within individual genomic subtypes. These included genetic alterations (DNA copy number alterations or sequence mutations), altered gene expression profiles, or both. These provide some of the first data that genomic profiling at diagnosis can further refine risk stratification."​

Dibash Kumar Das is a contributing writer.