A tumorigenic factor in childhood neuroblastoma identified!

Neuroblastoma accounts for 15% of total childhood cancer deaths. The survival rate of high-risk neuroblastoma patients is 50%.

For the first time, researchers have discovered that a gene called JMJD6 plays an important role in the most aggressive form of the disease. The research is published in the journal, Nature Communications.

It has long been known that a gain of the chromosomal region 17q is associated with the form of neuroblastoma with the poorer prognosis, however the particular genes within that chromosomal region that are important in neuroblastoma - and therefore are potential drug targets - have until now eluded researchers.

The research team found a candidate gene, called JMJD6, from a tumor data base of 209 patients, finding the gene active in more than one in four patients with the aggressive form of neuroblastoma.

The authors show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis.

In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression.

The researchers found that after three weeks of drug combination treatment, neuroblastoma tumor size was reduced by 80% compared to the control.

According the senior author similar drugs to the ones used in their experiments are currently in clinical trials for other cancers, making it more likely that this particular treatment strategy will be available for clinical trials of neuroblastoma.

https://www.nature.com/articles/s41467-019-11132-w