British Society for Haematology. Listening. Learning. Leading British Society for Haematology. Listening. Learning. Leading
02 December 2019

Scientists have identified a potential new drug target for an incurable subtype of acute lymphoblastic leukaemia (ALL), based on stopping the driving force behind it.

Researchers from the University of Zurich, Switzerland, examined the effects of the TCF3‑HLF fusion protein and how it disrupts normal blood cell development. They explain that TCF3‑HLF-positive leukaemia can be extremely resistant even to intensive chemotherapy or stem cell transplantation, and is currently incurable.

Dr Jean-Pierre Bourquin and colleagues discovered that TCF3-HLF activates many stem cell‑related genes at the wrong point in the blood development process, leading to malignant white blood cells and triggering leukaemia.

They also found that TCF3-HLF gathers more than 100 other proteins close to it when initiating abnormal gene transcription. By examining the function of the proteins in this genetic machinery, they identified key elements that could be targeted through therapy.

This highlighted the protein EP300 – a histone acetyltransferase  that boosts gene activation – as “a very promising target for therapy”.

A prototype drug, A‑485, which specifically inhibits EP300 hampered the gene activation process driven by TCF3‑HLF. The compound also delayed the progression of leukaemia in mice injected with human TCF3‑HLF-positive ALL cells.

Dr Bourquin believes: “It is therefore possible, in principle, to stop the fundamental driving force behind this leukaemia directly and thus develop a targeted type of therapy. The important thing now is to build a fuller picture of what goes wrong so that we can investigate the best possible way to combine specific modes of attack like this.”

 

Source:

Huang Y, Mouttet B, Warnatz HJ, Risch T, Rietmann F, Frommelt F, Ngo QA, Dobay MP, Marovca B, Jenni S, Tsai YC, Matzk S, Amstislavskiy V, Schrappe M, Stanulla M, Gstaiger M, Bornhauser B, Yaspo ML, Bourquin JP (2019) “The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability”, Cancer Cell, doi: 10.1016/j.ccell.2019.10.004