Co-corresponding author Chunliang Li, PhD, St. Jude Department of Tumor Cell Biology.
Scientists from St. Jude Children’s Research Hospital and collaborators have identified the RNA-binding protein RBM5 as a potential vulnerability in a set of difficult-to-treat childhood leukemias. They characterized how RBM5 regulates and interacts with the well-known cancer-driving protein MYC, which has long been considered impossible to effectively and directly target with existing cancer drugs. The findings, published today in Leukemia, present a new opportunity to develop targeted therapeutic interventions.
While most childhood leukemias now have high survival, a small subset with genetic rearrangements in the gene KMT2A have a poorer prognosis. This is in part because the oncogenes driving these cancers, such as HOXA9 and MYC, are not easily targeted pharmacologically due to their structure and fundamental role in normal cells.
In previous work, the researchers identified RBM5 as critical to HOXA9-driven malignant growth in patient-derived cell lines. In the current study, RBM5 was experimentally removed from both patient-derived primary cancer stem cells and genetic mouse models, to help researchers understand its contribution to leukemogenesis and whether it could be a useful target for therapeutic development.
“RBM5 showed multiple signs of being an ideal therapeutic target to explore in these leukemias,” said co-corresponding author Chunliang Li, PhD, St. Jude Department of Tumor Cell Biology. “When we removed RBM5 from leukemic stem cells, we doubled our mouse models’ survival, but when we removed it from normal blood-forming stem cells, we saw no effect on hematopoiesis, making it a promising candidate for developing more precise, less toxic therapies.”
Both findings are positive signs for drug development. The large increase in survival suggests the protein plays a profound role in cancer stem cells. The specificity suggests that targeting RBM5 would selectively affect leukemia cells, with minimal risk of toxicity in normal cells. The promise of these findings drove the investigators to better understand how RBM5 promotes leukemic growth.
RBM5 provides a new opportunity to affect the oncogene MYC
The researchers examined which genes and proteins were most impacted in cancer cells without RBM5, and MYC emerged as a top hit. MYC is one of the best-known cancer-driving proteins. It binds DNA to activate genes that promote cell growth, including regulatory regions that increase its own expression. This creates a positive feedback loop that helps sustain cancer.
The researchers found that immediate RBM5 degradation significantly reduced MYC protein levels in leukemia cells, leading to cancer cell death. “We found that without RBM5, MYC is destabilized and can no longer bind to its own gene’s regulatory regions,” Li said. “This disrupts MYC’s pro-growth feedback loop. Over time, the growth signaling is reduced, and leukemia cells die.”
To further explore the relationship between RBM5 and MYC, the researchers performed biochemical assays and found that RBM5 physically interacts with MYC. This finding provides a novel therapeutic opportunity that needs future testing.
“If we can find a way to disrupt the physical interaction between these two proteins, we may have found a way to destabilize MYC in leukemia cells,” Li said. “That gives us a new therapeutic direction for cancers like these difficult-to-treat leukemia subtypes.”
Authors and funding
The study’s other co-corresponding authors are Depei Wu and Peng Xu, Soochow University. The study’s co-first authors are Mengli Zhang, Soochow University; and Shaela Fields, St. Jude. The study’s other authors are Yuxin Ouyang, Ye Xin, Jianxiang Zhang, Hong Liu and Jia Chen, Soochow University; Jianfeng Shen, Shanghai Jiao Tong University School of Medicine; and Qiong Zhang and Beisi Xu, St. Jude.
The study was supported by the American Cancer Society (RSG DMC-135487), the V Foundation for Cancer Research (V2021-010) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.