Publication of Jakub Mieczkowski on pediatric brain tumors

14.02.2024

Jakub Mieczkowski, the head of Computational Biology group in our unit was the leader of the project on deciphering the “nucleosomal code” of changes in chromatin accessibility in brain tumor cells in response to epigenetic therapy for diffuse intrinsic pontine gliomas (DIPGs). It was carried out in cooperation with scientists from Poland, Canada, USA and Switzerland, and was financed, among others, by the National Science Center. The results of the project were published in the latest issue of Cell Reports (IF 9.995) in the paper H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells.

Diffuse intrinsic pontine gliomas are complex pediatric brain tumors. What makes them particularly difficult to treat is their location – they grow among important brain structures that control functions such as breathing and heartbeat.

– A characteristic feature of these tumors is their invasion into surrounding tissues, which makes their surgical removal almost impossible – explains Jakub Mieczkowski – Unfortunately, patients with DIPG have a very poor prognosis, with survival measured in months, highlighting the urgent need for effective treatment options.

More than 80% of patients with DIPG have a mutation in a histone protein called H3.3, replacing a lysine with methionine at position 27 (H3.3K27M). Histone proteins bind to the DNA chain and thus play a key role in regulation of gene expression. The H3.3K27M mutation in DIPG disrupts the proper functioning of cells, leading to uncontrolled tumor growth.

– The results of our research is a step forward in understanding the complexity of gliomas in children. Although they do not yet allow for the introduction of a new therapy, this study sheds new light on potential therapeutic paths to counteract the H3.3K27M mutation. It contributes to a broader discussion on improving the treatment strategy for brain tumors in children – explains Prof. Mieczkowski.

One of the potential options for DIPG therapy is the use of histone deacetylase (HDAC) inhibitors, which were the subject of this project. The task of histone deacetylases is, among others, modification of histones at position 27 and thus affecting cell functioning. The tested HDAC inhibitors suppress the physiological process of histone modification, which provides therapeutic opportunities in cancer cells.

The positive results of these preclinical studies provide the basis for further analyzes of their effectiveness and safety in in vivo studies.

Here you can listen to the interview with Jakub Mieczkowski: https://lnkd.in/diCzBqj4

Kuba Mieczkowski