Researchers have unveiled a groundbreaking change in how we understand T-lineage acute lymphoblastic leukemia (T-ALL), a form of cancer that is aggressive and high-risk. This new insight emphasizes that many of the genetic changes related to T-ALL often occur in the non-coding parts of our DNA.
A group of scientists from the Children’s Hospital of Philadelphia (CHOP), St. Jude Children’s Research Hospital (St. Jude), and the Children’s Oncology Group (COG) announced this vital shift today. Their collaborative research, backed by the Gabriella Miller Kids First Pediatric Research Program (Kids First) and the National Institutes of Health (NIH) Common Fund, was released in the journal Nature.
Although many young patients with T-ALL initially respond well to treatment, those who experience relapse or have treatment-resistant forms of the disease often face grim outcomes. The rapid progression and aggressive nature of T-ALL, along with the limited knowledge regarding its genetic foundations, prompted researchers to seek new and improved diagnostic and therapeutic strategies.
According to Dr. David T. Teachey, an attending physician, the Director of Clinical Research at the Center for Childhood Cancer Research at CHOP, and Chair of the Acute Lymphoblastic Leukemia committee in COG, “This study marks a groundbreaking progression as it comprehensively analyzes the entire genome, revealing vital insights from over 1,300 children, adolescents, and young adults diagnosed with T-ALL. Our findings greatly advance clinical practice; the aim of treating T-ALL is to prevent relapses, effectively identifying patients at heightened risk.” The data enables us to classify patients based on their risk of relapse, allowing for treatment with newer or alternative therapies.
Earlier studies fell short in pinpointing crucial genetic alterations in T-ALL as they mainly concentrated on the coding regions of the genome, which are the parts that encode proteins essential for cellular composition. Notably, only about 1% of DNA comprises the coding portion, while the remaining 99% is referred to as non-coding DNA.
Once dismissed as irrelevant, non-coding regions are now understood to be critical for regulating numerous biological processes. They play a role similar to a traffic guide, directing cells when to produce specific proteins.
In their study, researchers examined over 1,300 patients enrolled in the COG AALL0434 clinical trial, analyzing both tumor and non-tumor genomes for every participant. Although prior research had suggested that non-coding DNA might be influential in T-ALL, this study is the first to confirm this on such a vast scale.
The researchers discovered that around 60% of the genetic alterations driving T-ALL originate from non-coding regions. This revelation fundamentally changes the perception of T-ALL, providing deeper insights into its biological makeup and opening the door for innovative therapies, including new immunotherapies being developed at CHOP and St. Jude.
In the past, T-ALL patients were classified by risk based on their treatment responses and immunophenotype, which is characterized by analyzing cell surface proteins during diagnosis. While this approach aided the classification of T-ALL subtypes, it has not consistently determined which patients might have favorable outcomes. The newly obtained comprehensive data explains why, advocating for a genomic methodology to replace traditional immunophenotypic classification. Consequently, researchers have created models that accurately classify T-ALL patients based on genetic data and treatment responses, and they are currently validating these models using samples from the upcoming COG T-ALL trial.
Dr. Charles Mullighan from St. Jude Children’s Research Hospital noted, “It was remarkable to see the prevalence of non-coding changes and the extent of enhancer disruption events, whether through hijacking or modification of existing enhancers, or the creation of new enhancers. With this enhanced understanding, we can refine our lab work and focus on these relevant alterations to develop appropriate diagnostic tests.”
The study has categorized T-ALL into 15 distinct subtypes based on their unique gene expression and genomic drivers, including previously unidentified types. The research also improved our understanding of known subtypes and demonstrated how driver mutations, alongside other genetic alterations and the initial cell type, work collectively to define genomic subtypes along with their clinical and biological traits. A critical finding linked the specific type of gene adaptations to the prognosis and treatment outcomes in T-ALL, indicating that it matters not just which genes are altered, but also the nature of those alterations for a diagnosis.
Dr. Teachey emphasized, “It’s crucial that future research expands on this approach. These results provide a solid foundation for enhancing patient outcomes and striving for cures for a greater number of children and adults afflicted with T-ALL.”
