KDM2B revealed as a selective dependency in high-risk medulloblastoma subgroups

Targeting KDM2B, or downstream protein complexes it recruits, may present a vulnerability in high-risk medulloblastoma subgroups that currently lack targeted therapies. This finding comes from a study led by St. Jude Children’s Research Hospital and Hopp Children’s Cancer Center Heidelberg (KiTZ). The researchers found that Group 3 and Group 4 medulloblastomas depend on the protein KDM2B for growth, and that removing it slowed tumor growth in preclinical models. The findings were published today in Nature Genetics. 

Medulloblastoma is one of the most common malignant brain tumors in children and comprises four major subgroups. Group 3 and Group 4 medulloblastomas are high-risk subgroups and lack targeted therapies. As a result, these tumors often require intense treatments that can cause substantial long-term side effects, underscoring the need to discover more precise therapeutic approaches.  

Although epigenetic deregulation that disrupts normal brain development is believed to drive medulloblastoma formation, the underlying mechanisms remain incompletely understood. To better understand the mechanisms and identify vulnerabilities, St. Jude and KiTZ researchers performed a comprehensive characterization of histone post-translational modifications, changes to which could affect gene expression without changing DNA sequences, in patient samples of every subgroup. They then looked for what genes regulate those histone modifications. They discovered that KDM2B, an epigenetic regulator that is highly expressed in Group 3 and Group 4 tumors, is essential for tumor growth. Removing the gene for KDM2B or degrading the protein suppressed tumor growth and prolonged survival in preclinical models. 

“We found that select medulloblastoma groups require KDM2B to grow using preclinical models,” said corresponding author Paul Northcott, PhD, St. Jude Center of Excellence in Neuro-Oncology Sciences (CENOS) director and Department of Developmental Neurobiology member. “This gives us a potential future therapeutic opportunity that may selectively suppress the growth of Group 3 and Group 4 medulloblastomas.” 

Creating a resource to sort through medulloblastoma’s epigenetics 

For Northcott, the finding concludes a project that began years ago during his postdoctoral work. “When we first started sequencing medulloblastoma genomes, we saw an enrichment in chromatin-modifying genes, but it was unclear how we could exploit them,” Northcott said. “Almost 15 years later, we were finally able to find and dig into that signal.” 

During that time, scientists found alterations to proteins that modify chromatin, the structural organization of DNA, affected genes’ expression that were critical to medulloblastoma development. However, identifying which of those proteins might create therapeutic vulnerabilities required a deeper view of how epigenetic regulation differs across tumor subgroups. 

To achieve that, the researchers performed the largest analysis of its kind in 52 primary patient samples from this rare pediatric brain cancer, with multiple samples for each of the four major subgroups. They profiled six distinct histone modifications and used chromatin state as a functional readout, creating a comprehensive resource for the field. 

The team then used this resource to search for strong subgroup-specific signals that could point to targetable vulnerabilities. 

“We first found a recurrent, aberrant epigenetic signature in Group 3 and Group 4 tumors,” said first author Ran Tao, PhD, St. Jude Department of Developmental Neurobiology. “When we asked, ‘What chromatin-modifier contributes to this?’ KDM2B came out. We then spent years of work investigating how KDM2B controls tumor growth and addressed the underlying molecular mechanisms.”