24 August 2018

An international team of scientists has reported what appears to be a new weakness in mixed lineage leukaemia cells.

Reporting in Proceedings of the National Academy of Sciences, the authors looked at a protein called lens epithelium derived growth factor, or LEDGF/p75, which contributes to the regulation of gene expression. LEDGF/p75 works by tethering other proteins onto chromatin, but this process is ‘hijacked’ in HIV and mixed lineage leukaemia.

Until now, little was known about how the interaction of LEDGF/p75 with its binding partners is regulated.

By in-depth structural analysis of LEDGF/p75, the team showed that its modification by the enzyme casein kinase is crucial in regulating these interactions.

The team also showed that destroying regulatory sites in one of the LEDGF/p75 interaction partners, reduces the ability of leukemic cells to remain in a cancer-like state. This interaction is only necessary for cancer cells, so could represent a target for possible treatment.

Dr Vaclav Veverka of the Institute of Organic Chemistry and Biochemistry in Prague, Czech Republic, and colleagues explain that little is known about the biological regulation of LEDGF/p75. This has limited the chances of medical treatments targeting the childhood disease.

The study also showed that LEDGF/p75 "participates in a much larger network of factors involved in transcription elongation than what was previously recognised".

The ground-breaking study will assist the development of novel therapeutic strategies for mixed lineage leukaemia.

Dr Veverka said: "The power of structural biology is the ability to visualise the molecular interactions that contribute to human disease."

Source: Sharma, S., Čermáková, K., De Rijck, J., Demeulemeester, J., Fábry, M., El Ashkar, S., Van Belle, S., Lepšík, M., Tesina, P., Duchoslav, V. and Novák, P., 2018. Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proceedings of the National Academy of Sciences, 115(30), pp.E7053-E7062.

Link: http://www.pnas.org/content/early/2018/07/10/1803909115/tab-article-info


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