A recent study conducted by scientists at St. Jude Children’s Research Hospital has provided significant insights into the genes directly regulated by the HOXA9 protein, which is associated with high-risk pediatric leukemias. High-risk leukemias, especially the MLL-rearranged (MLL-r) subtype, often exhibit overexpression of the homeodomain transcription factor HOXA9, for which there are currently no targeted therapies available.
This groundbreaking research lays the groundwork for understanding the regulation network of HOXA9 and discovering new drug targets downstream of this protein. The findings of this study were published in Nature Communications on November 28.
HOXA9 is a transcription factor, a type of protein that binds to DNA and controls the expression of other genes. Overexpression of HOXA9 is a characteristic feature in various cancers, including high-risk leukemias such as MLL-r leukemia. The identification of genes regulated by HOXA9 could potentially uncover new avenues for leukemia treatment by disrupting the role of this protein in cancer growth and survival.
However, studying the downstream regulation network of HOXA9 has been challenging due to technical limitations. In this study, the researchers at St. Jude employed a novel system to identify the genes regulated by HOXA9.
“The St. Jude team confirmed two major known targets, FLT3 and CDK6,” explained corresponding author Chunliang Li, Ph.D., from the St. Jude Department of Tumor Cell Biology. “Both genes can be therapeutically targeted by drugs, which have shown promising outcomes in preclinical models with HOXA9 overexpression. Our results provide direct evidence supporting the regulation of FLT3 and CDK6 enhancers through HOXA9.”
In addition to these well-studied genes, the scientists discovered 227 other target sites where HOXA9 binds. Many of these sites were located in noncoding regulatory regions, which are likely enhancers. The top 10 candidates were validated through cell-based experiments in collaboration with computational biologists from the St. Jude Center for Applied Bioinformatics.
Several of these identified targets corroborated previous findings involving FDA-approved drugs, lending credibility to the other results from this study and suggesting that they may serve as potential targets for novel leukemia drugs.
To conduct this study, the St. Jude researchers established a TetOn-inducible system to express tagged HOXA9 in MLL-r leukemia cell lines. Using this innovative research tool, followed by chromatin immunoprecipitation sequencing (ChIP-seq) technology, they successfully identified the specific sites where HOXA9 binds to DNA in MLL-r leukemic cells.
Co-first author Shaela Fields from the St. Jude Department of Tumor Cell Biology emphasized, “Using state-of-the-art research tools and elegant model systems, we now have a better understanding of how HOXA9 functions in high-risk leukemia cells. With this information, we can embark on the lengthy process of discovering and developing new drugs to improve the health of our patients.”
HOXA9 has long been known to be overexpressed in high-risk pediatric leukemias. However, its study and targeting have been historically challenging. The HOX protein family consists of 39 members that are very similar to one another, making it difficult to distinguish between them using current techniques. Additionally, other members of the HOX family could potentially compensate for the function of HOXA9 when it is targeted.
In light of these challenges, the researchers devised a system to identify the genes specifically bound by HOXA9 in a particular leukemia subtype (MLL-r) by attaching a tag to HOXA9.
Dr. Li illustrated the concept using an analogy, stating, “Imagine you are in a dog park and need to find a certain golden retriever, but there are a bunch of them running around, and you don’t know which one is yours because all the dogs look the same. If you put a neon pink harness on your dog beforehand, it’s easy to find among the group. That is how we could track everywhere HOXA9 went.”
The small tag does not interfere with the regular function of HOXA9 and enables easy tracking of the protein in cells. The researchers then sequenced the DNA attached to the tag to identify the genes bound by HOXA9 that are relevant to leukemia, thus providing a relatively small list of genes that could be potential targets for therapeutic development.
Shaela Fields added, “By comparing to controls, we narrowed down hundreds of thousands of targets to just over two hundred. Now, as we investigate the regulation mechanism and network of HOXA9, and delve into what’s happening in the cells, we hope to find ways to improve outcomes for children with high-risk cancers.”
This ground-breaking research not only uncovers the genes regulated by the oncogenic HOXA9 protein but also lays the foundation for future drug development targeting these genes. By understanding the regulation network and identifying novel drug targets downstream of HOXA9, this study opens up new possibilities for improving the treatment of high-risk pediatric leukemia.
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