Researchers at St. Jude Children’s Research Hospital have found that certain DNA variants in the non-coding regions of the genome play a role in chemotherapy resistance in acute lymphoblastic leukemia (ALL). This discovery has led to a better understanding of the underlying mechanism of resistance to treatment. The team used new technologies to overcome previous limitations in understanding the non-coding genome, and this approach could potentially be applied to other types of cancer and diseases as well.The latest study was released today in Nature Communications.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Thanks to modern therapy, survival rates are now over 94%. However, those who have relapsed or recurrent disease, often due to chemotherapy resistance, have a much lower survival rate of 30-40%.
The scientists examined resistance variants found in the non-coding genome, which makes up 98% of DNA and does not contain genes. Previous efforts to identify resistance mechanisms to chemotherapy focused on DNA that encoded genes. Looking directly at genes is simpler because non-coding DNA may have intricate associations with gene function, but the St. Jude team has proven that it is feasible. “We have shown that we now possess the means to identify relevant non-coding genetic factors that contribute to chemotherapy resistance,” stated lead author Daniel Savic, PhD, from the St. Jude Department of Pharmacy and Pharmaceutical Sciences. “The ultimate goal is to comprehend the mechanisms of drug resistance so that we can create new treatments and enhance existing chemotherapies tailored to each individual’s unique genetic composition.” The focus is on delving into non-coding DNA to uncover the underlying cause of chemotherapy resistance.”According to co-first author Jackson Mobley, PhD, of the St. Jude Department of Pharmacy and Pharmaceutical Sciences, nearly 98% of the genome contains instructions. In his analogy, Mobley explains that genes can be compared to the iron bars, wires, and concrete used in building construction, while non-coding DNA serves as the blueprints. The research team identified small variations in the blueprints that can influence an individual’s response to certain therapies.”
The group utilized advanced technologies to investigate non-coding resistance variants, analyzing patient samples and clinical data on treatment outcomes. Unlike previous research that focused on single genes or variants, this study incorporated high-throughput DNA sequencing methods.The St. Jude researchers used advanced methods to conduct extensive variant screens, allowing them to test over 1,600 variants at once to determine their functionality. This approach led to the discovery of over 500 functional non-coding DNA variants linked to chemotherapy resistance, representing the most extensive investigation of its kind in ALL. Co-first author, Kashi Raj Bhattarai, PhD, from the St. Jude Department of Pharmacy and Pharm, emphasized the significance of this work in identifying inherited non-coding variants associated with pharmacological traits.aceutical Sciences. “Our research confirmed that the identified variations also have a similar impact on both cell lines and patient samples.”
An innovative method of resistance
By examining numerous non-coding variations simultaneously, the scientists were able to identify the most significant ones across various subtypes of ALL and link them to a specific gene using advanced 3D genome mapping technologies. By uncovering the mechanism by which variations in the non-coding genome influence the activity of target genes, they can determine how it impacts the response of cancer to treatment.
For instance, the primary variation from the study led to the identification of a new resistance mechanism.The resistance mechanism was against the chemotherapy drug vincristine. The researchers studied how the DNA with the functional variant was physically connected to its target gene and which transcription factors were involved. The variant was found to be bound near the gene for EIF3A, which is known to play a role in cell proliferation and survival. By deleting the DNA containing the variant or reverting the mutation to the original sequence, the cells’ sensitivity to the chemotherapeutic agent vincristine could be altered.
This study demonstrates how non-coding DNA can impact drug resistance.research will help unlock the potential of the non-coding genome and shed light on the role of NA variants in various traits and conditions, ultimately advancing genomics research across different fields.” Savic and his team’s findings, which were published in the journal Nature Genetics, offer valuable insights into the complex relationship between non-coding DNA variants and traits like chemotherapy resistance. This breakthrough has the potential to revolutionize genomics research and pave the way for new treatments and interventions in the future.The research can be used to improve the outcomes of medical treatment for all patients.
