Epigenetic expression in T cell leukaemia

Dr Sinisa Dovat - Penn State Cancer Institute, Hershey, USA

My presentation is about epigenetic regulation of gene expression in T-cell leukaemia. Specifically we are talking about how tumour suppressor Ikarus, IKZF1, epigenetically regulates gene expression. Ikarus is a tumour suppressor and deletion of one copy of Ikarus is associated with about 5% of T-cell ALL and about 11% of early T-cell precursors. In B-ALL deletion of Ikarus is associated with poor prognosis so Ikarus is quite an important tumour suppressor.

We had a system in which mice who are deficient for Ikarus develop T-cell leukaemia. Once you reintroduce Ikarus in these leukaemia cells you arrest the cells’ proliferation and you induce differentiation. What we did, actually, we compared the epigenetic landscape signature in leukaemia cells and following Ikarus introduction. What we found is several unexpected and new functions of Ikarus in tumour suppression which is specifically that Ikarus induces formation of de novo enhancers, also super-enhancers and also activates [?? 1:28] enhancers or activates de novo enhancers. So this is a completely different way of regulation of gene expression than we knew so far.

How can we target this tumour suppressor?

Tumour suppressors typically are very difficult targets. In this case how we can target, and we showed that a couple of years ago, is that we found that the Ikarus protein is inactivated in both B-cell acute lymphoblastic leukaemia and T-cell acute lymphoblastic leukaemia. It’s inactivated by phosphorylation by oncogenic casein kinase 2, CK2 kinase. So by targeting the CK2 kinase we can actually restore Ikarus function and reactivate Ikarus to restore its tumour suppressor function.

Might it play a role in treating other types of cancer?

It’s mostly leukaemia that we know. We know that it plays a role in B-cell ALL, T-cell ALL, most likely AML as well and pituitary adenoma for sure. There are indications it might play a role in neuroblastoma as well and several other types of cancer but that’s still unsure, it’s uncertain.

What are the next steps?

The next step is several lines. Certainly we plan to continue our epigenetic studies since now we discovered all these new functions. We want to take more into the human primary cells, both B-cell ALL and T-cell ALL. On the other side, we plan to refine our inhibitors of CK2 and to make better drugs for that. Current existing drugs, I believe that they are heading towards phase I trial for haematopoietic malignancies.

Is there anything you would like to add?

Thank you very much for organising this meeting. This is an amazing meeting with all experts, world experts, in acute lymphoblastic leukaemia together. This is quite impressive and it’s a pleasure to participate.