Co-first author Shaela Fields, and co-corresponding author Chunliang Li, PhD, both of the St. Jude Department of Tumor Cell Biology.
Scientists from St. Jude Children’s Research Hospital and collaborators have discovered that the RNA-binding protein MBNL1 promotes the growth of a form of childhood leukemia characterized by KMT2A gene rearrangements. The finding identifies MBNL1 as a promising therapeutic target for future drug development. The results were published today in Science Advances.
Although survival for childhood leukemia has improved dramatically, cancers containing rearrangements in the gene KMT2A remain among the most difficult to treat. Patients who relapse often face poor outcomes, and the mutant proteins that drive the disease are not directly targetable with existing therapies. To identify alternative vulnerabilities, researchers searched for proteins that help maintain the activity of FLT3, a key oncogene that drives KMT2A-rearranged leukemia.
“We found that KMT2A-rearranged leukemia cells rely on MBNL1 to maintain expression of FLT3,” said co-corresponding author Chunliang Li, PhD, St. Jude Department of Tumor Cell Biology and the Department of Oncology. “When we investigated how this occurred, we uncovered an unexpected mechanism that may provide several new opportunities for therapeutic intervention.”
When the researchers removed MBNL1, KMT2A-rearranged cells showed a significant growth impairment. In contrast, eliminating MBNL1 in other cancer types had little effect, a positive sign for the context-selective role.
“Because this dependency appears unique to KMT2A-rearranged leukemia, our results hint that MBNL1 has real therapeutic potential,” said co-first author Shaela Fields, St. Jude Department of Tumor Cell Biology. “Targeting MBNL1 may help shut down leukemia, while having minimal effects on normal cells.”
While the researchers had identified MBNL1’s significance, they needed to understand how it promoted leukemia growth to better determine its potential as a therapeutic target.
An RNA-binding protein with an unexpected DNA-binding role
Scientists have long known that MBNL1 binds to RNA and regulates splicing events. What remained unclear was how it regulated FLT3 expression, a process that likely requires interaction with regulatory DNA.
To find out, the researchers captured the structure of MBNL1 interacting with DNA, then performed biochemical analyses. These tests revealed that the protein had an unanticipated ability to bind a DNA region that regulates FLT3 expression. Also unexpectedly, it did not bind to DNA’s normal double-stranded form, but exclusively to single-stranded DNA.
“We saw that MBNL1 hijacks an existing process in KMT2A-rearranged leukemia cells to keep FLT3 activated,” Fields said. “It takes a door that’s already open and acts as a doorstop, preventing it from closing.”
When genes are activated, portions of DNA temporarily open their two strands, exposing single strands so proteins can bind and transcribe RNA from those genes. The researchers found that in KMT2A-rearranged leukemia, mutant KMT2A proteins help initiate FLT3 expression by exposing a specific regulatory DNA region as a single-stranded DNA, which MBNL1 binds to, if available, and keeps active.
Multiple opportunities for therapeutic intervention
When the scientists removed MBNL1’s ability to bind DNA, or removed the region of DNA that bound to MBNL1, KMT2A-rearranged cancer cells had less growth. This is attractive for drug development, as it means that both the MBNL1 protein and the specific DNA sequence may be pursued as targets in the future.
“We are optimistic that MBNL1 is a good target, either directly or through the DNA-binding mechanism,” Li said. “Regardless, by describing the details of how it, and other proteins, support this cancer’s growth, we are one step closer to finding a better treatment for children with KMT2A-rearranged leukemias.”
Authors and funding
The study’s other co-first author is Meixia Che, Nanjing University. The study’s other co-corresponding author is Yajun Jiang, Nanjing University. The study’s other authors are Mengli Zhang and Peng Xu, Soochow University; and Siqi Yi, Judith Hyle, Beisi Xu and Yong Cheng, St. Jude.
The study was supported by grants from the V Foundation for Cancer Research (V2021-010), the American Cancer Society Research Scholar Grant (RSG DMC-135487) 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.