While blood cancers can often be temporarily controlled, a majority relapse with dire consequences for patients. There is urgency for new treatments, and the Josep Carreras Leukaemia Research Institute is at the forefront of international efforts to find new druggable targets and exploit them therapeutically.

To this end, the team of Dr. Marcus Buschbeck, head of the Chromatin, Metabolism and Cell Fate lab at the Josep Carreras Institute, is searching for novel drug targets related to chromatin, the biochemical compartment in which cells store their genetic information and which directs how genes are regulated.

Histones are a broad family of regulatory proteins essential for chromatin structure and genome stability. Indeed, mutations affecting histones are known to contribute to blood cancers and, therefore, certain histone genes are also potential therapeutic targets. This is of great importance since disruption of chromatin functions is known to be a biological hallmark of blood cancers.

However, therapeutic targeting of histones had long been considered impossible, since most histones are essential for cell survival and drugs inhibiting them were expected to have intolerable side effects in patients. This is unfortunate “since it deprives of the opportunity to develop new medicines against this important blood cancer driver mechanism” said Ari Melnick, Director of the Josep Carreras Institute.

There is promise along these lines however, since Dr. Buschbeck identified a subgroup of histones called macroH2A as possible therapeutic candidates. Past research from the Buschbeck lab and others have shown a link between macroH2A and Acute Myeloid Leukaemia, adding arguments to investigate macroH2A in deep.

In a series of experiments, recently published in the prestigious scientific journal Science Advances, Buschbeck and colleagues tested the consequences of removing each of the three variants of macroH2A in healthy mice, a first step towards demonstrating if these are suitable drug targets for leukaemia patients. The experiments were spearheaded by Dr. René Winkler and several experiments were conducted in a collaboration with physiology experts at the Helmholtz Center Munich and the German Mouse Clinic, a facility which can monitor over 500 parameters in mice, enough to find even the slightest effect of an experimental treatment.

The results show that, quite surprisingly, the investigated mice have no obvious adverse effects. The most remarkable observation was a mild kidney condition after the removal of the macroH2A1.1 histone variant. This condition was found to be the consequence of a metabolic imbalance, where mice shifted their overall metabolization from fat to sugar. Based on this finding, researchers were able to rescue this kidney condition with small diet adjustments that did not pose any thread to the animals whatsoever.

Overall, the research team concludes that targeting macroH2A histone variants would be safe for patients. These results have led to the creation of a whole new research line at the Josep Carreras Leukaemia Research Institute and its international partners in which researchers broadly test macroH2A variants as potential drug targets in leukaemia and other blood cancers.

This research has been partly funded by the European Commission, the Catalan Government and the German Federal Ministry Education and Research, the German Research Foundation (DFG), the German Center for Diabetes Research, La Caixa Foundation, the Asociación Española Contra el Cáncer (AECC), the Josep Carreras International Foundation and the American National Institutes of Health. No generative AI tools have been used in the writing of this news piece.

Reference article: René Winkler et al. “Loss of histone macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization”. Sci. Adv., Vol 11, Issue 43. https://doi.org/10.1126/sciadv.adz1242