Researchers have uncovered that T-lineage acute lymphoblastic leukemia (ALL) may be frequently driven by genetic changes in noncoding portions of the DNA, according to a recent study published by Pölönen et al in Nature. The investigators believe these findings may lead to a paradigm shift in understanding of the disease.
Background
T-lineage ALL is an aggressive and high-risk type of hematologic malignancy.
Pediatric, adolescent, and young adult patients with T-lineage ALL typically respond well to initial treatment. However, those who relapse or have treatment-resistant disease often have a poor prognosis. Given the aggressive nature and rapid progression of the disease and limited understanding of the genetic basis of T-lineage ALL, there is currently an urgent need for new and effective approaches to diagnosis and treatment.
Prior research has been unable to identify important genetic changes in T-lineage ALL, focused instead on the coding genome. However, just 1% of DNA is coding, whereas the other 99% is noncoding. Researchers now recognize that the noncoding region, once considered useless, plays a key role in regulating biological processes, signaling the cell when to produce certain proteins.
“This [study] is the first to transcend previous barriers and comprehensively profile the whole genome, uncovering critical insights in more than 1,300 children, adolescents, and young adults with T-[lineage] ALL,” explained senior study author David T. Teachey, MD, Director of Clinical Research and an attending physician at the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia as well as Chair of the Acute Lymphoblastic Leukemia disease committee in the Children’s Oncology Group (COG).
Study Methods and Results
In this study, the researchers sequenced the tumor and nontumor genomes of 1,300 patients with T-lineage ALL who were treated as part of the COG AALL0434 clinical trial. They found that approximately 60% of the genetic changes driving T-lineage ALL cancer cells were noncoding changes.
Although researchers previously suspected that noncoding DNA in T-lineage ALL may be critical to disease progression, the findings could potentially alter the way researchers understand the disease and its biology and lead to innovative treatments such as immunotherapies.
Traditionally, patients with T-lineage ALL have been categorized by risk based on their response to therapy and immunophenotype, which profiles cell surface proteins as part of the diagnostic workup. Cell surface protein expression helps define T-lineage ALL subtypes, but it hasn’t proven effective in consistently identifying which patients may have a good prognosis. The new comprehensive data suggested that a genomic approach replace the current immunophenotypic classification.
The researchers were able to classify T-lineage ALL into 15 subtypes with distinct gene expression and genomic drivers, including previously undefined subtypes. They refined the classification of known subtypes and demonstrated that driver lesions, other genetic changes, and the original cell type may work together to define the genomic subtype and the clinical and biological characteristics of a condition. The researchers also observed a significant link between the type of gene alterations and outcomes in T-lineage ALL, revealing that knowing which gene is altered in the cancer cells and how it is altered may help define patients’ prognoses.
Conclusions
“These findings are a significant clinical advancement, as the goal in treating T-[lineage] ALL is to prevent relapse, which requires identifying the patients most at risk. [These] data now make it possible to risk stratify patients with T-cell leukemia, identifying those with a high-risk of relapsing, so we can treat them with newer or alternative medicines,” Dr. Teachey highlighted.
“It was striking how abundant these noncoding changes were and how many of them were enhancer perturbation events, whether it was hijacking or co-option of an existing enhancer or changes that generated a new enhancer,” emphasized co–study author Charles Mullighan, MBBS, MD, Deputy Director and member of the Department of Pathology at the Comprehensive Cancer Center at St. Jude Children’s Research Hospital. “We now have a much stronger framework to take these alterations back to the laboratory and say now we've got better information to build the right models to understand the biology, and then to test therapy. We have very clear information that these are the sorts of alterations that [researchers] need to focus on to build a diagnostic test,” he added.
As a result of the findings, the researchers developed models that incorporated genetics and response to treatment—with the goal of risk stratifying patients with T-lineage ALL accurately. They are currently in the process of validating results using patient samples from the next COG trial of T-lineage ALL.
“Future research must continue to determine broader applications for this approach. These findings offer a strong roadmap for improving patient outcomes and curing more [pediatric] and adult [patients] with T-[lineage] ALL,” concluded Dr. Teachey.
Disclosure: The research was supported by the Gabriella Miller Kids First Pediatric Research Program, the National Institutes of Health Common Fund, the National Cancer Institute, Alex’s Lemonade Stand Foundation, the Leukemia and Lymphoma Society, Hyundai Hope of Wheels, the St. Jude Chromatin Collaborative, the St. Jude Children’s Research Hospital Hematological Malignancies Program Garwood Fellowship, and the American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit nature.com.
