Discovery of Key Genetic Driver in Neuroblastoma Paves Way to New Therapeutic Approaches
Alternative treatments with fewer long-term side effects are urgently needed
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Led by the Children’s Cancer Institute, a multi-institutional study published in Nature Communications has shown for the first time that a gene known as Runx1t1 is essential for the development of the childhood cancer, neuroblastoma.
A new way to target neuroblastoma and potentially other cancers
Neuroblastoma is the most common solid tumor of infancy. Responsible for approximately 15% of childhood cancer-related deaths, it grows particularly aggressively in children whose tumors display high levels of the MYCN oncogene through amplification.
In these high-risk cases, the survival rate is only 50%, with survivors often suffering serious long-term health problems as a result of the intensive treatment they received. Alternative treatments with fewer long-term side effects are urgently needed.
The critical role of Runx1t1
Our study took a fresh approach to finding a way to target neuroblastoma. In the past, research has focused on the MYCN oncogene, since high levels of MYCN are known to be an independent marker of poor prognosis. In this study, we used an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice to look for other genes critical to MYCN-driven tumorigenesis. We then used a knockout mouse model to demonstrate the effect of silencing the critical gene we identified, as well as liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP) to define its interactome (protein binding partners).
The key findings of the paper were:
- “Knocking out” or silencing the Runx1t1 gene completely prevented the development of tumors in mice bred to develop neuroblastoma, and strongly inhibited the growth of human neuroblastoma cells in culture.
- Runx1t1 was found potentially to play an important role in adult small cell lung cancer and rhabdomyosarcoma, two other cancers that display high levels of Runx1t1.
- Silencing Runx1t1 not only inhibited the growth of neuroblastoma cells, but also appeared to make these cells more visible to the body’s immune system.
Opening previously unexplored avenues for cancer prevention and therapy
We concluded from our study that Runx1t1 is essential for MYCN-driven tumorigenesis. This is a major finding that opens up previously unexplored avenues for the development of new therapeutic and prevention approaches to neuroblastoma, and potentially other cancers as well.
Our work suggests that the mechanism by which Runx1t1 contributes to neuroblastoma tumorigenesis is by maintaining primitive nerve cells (neuroblasts) in an undifferentiated state. A complex of proteins involving Runx1t1 acts epigenetically (that is, by adding or removing DNA modifications without changing the DNA sequence) to suppress the activity of genes important in cell-fate determination. This allows MYCN to drive increased proliferation of these cells, a process known as neuroblast hyperplasia, which is an established pre-requisite for the development of tumors in neuroblastoma-prone mice. In our current study, we found that silencing Runx1t1 completely reverses this MYCN-driven hyperplasia.
Our findings have important implications for future research focused on disease-driving genes. Our results suggest that, using current gene technology, potentially critical genes are going undetected.
In the case of neuroblastoma, MYCN is well known as a master gene regulator, whose action involves binding to specific DNA regions to control the transcription of a large number of genes. One of the reasons that Runx1t1 has remained elusive and not been previously identified from gene sequencing studies is that MYCN does not transcriptionally regulate Runx1t1, nor does Runx1t1 itself regulate MYCN. Rather, high levels of MYCN drive the machinery that causes high levels of Runx1t1 protein to be produced. It is highly likely that there are many other genes regulated in a similar fashion.
It should be noted that the main findings from this research were obtained from a genetically engineered mouse model of human neuroblastoma and it remains to be seen whether they will be directly translatable to the human disease. In addition, at the current time, there is no drug or specific inhibitor of Runx1t1 that is approved for clinical use.
Targeting Runx1t1 for therapeutic benefit
Having shown that Runx1t1 is critical to the initiation and progression of neuroblastoma, we are now working with collaborators to develop a novel drug to target this gene. Development of a safe and effective Runx1t1 drug would not only have application in treating established disease but ultimately in tumor prevention.
Also under further investigation is the finding that, in addition to inhibiting the growth of neuroblastoma cells, silencing Runx1t1 also appears to make these cells more visible to the body’s immune system, and therefore potentially more susceptible to immunotherapy.
Reference: Murray JE, Valli E, Milazzo G, et al. The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis. Nat Commun. 2024;15(1):5585. doi:10.1038/s41467-024-49871-0
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