A groundbreaking study has identified a promising new therapeutic target for treating acute myeloid leukemia (AML), a challenging blood cancer. Researchers at the Josep Carreras Leukaemia Research Institute, led by Dr. Marcus Buschbeck and Dr. René Winkler, have discovered that targeting a specific group of histones, known as macroH2A, is not only safe but could also pave the way for innovative treatment options.
The study confirms that removing any of the three proteins belonging to the macroH2A family in mice does not have significant adverse effects on their health. This finding is particularly important as AML, while often controllable in the short term, frequently relapses, resulting in serious consequences for patients. The urgent need for new treatment strategies has made the research conducted at the Josep Carreras Institute critical in the ongoing battle against blood cancers.
Significance of MacroH2A in Blood Cancer Research
Chromatin, the structure that organizes DNA within cells, plays a vital role in gene regulation. Histones, including macroH2A, are essential proteins that help maintain chromatin structure and genome stability. Mutations in histones are implicated in various blood cancers, making them potential therapeutic targets. Historically, targeting histones has presented challenges, as most are crucial for cell survival and any drugs designed to inhibit them were expected to cause intolerable side effects.
Dr. Ari Melnick, Director of the Josep Carreras Institute, emphasized the importance of this research, stating, “It deprives us of the opportunity to develop new medicines against this important blood cancer driver mechanism.” However, the identification of macroH2A as a candidate for targeted therapy marks a significant shift in this perspective.
In their recent publication in Science Advances, Dr. Buschbeck and his team conducted experiments to assess the effects of removing each variant of macroH2A in healthy mice. This was a crucial step in determining whether macroH2A could be a viable drug target for leukemia patients.
Experimental Findings and Future Directions
The experiments, conducted in collaboration with specialists from the Helmholtz Center Munich and the German Mouse Clinic, monitored over 500 parameters in the test subjects to detect any potential side effects. Remarkably, the results showed no significant negative outcomes in the mice. The only notable observation was a mild kidney condition linked to the removal of the macroH2A1.1 variant. This condition stemmed from a metabolic imbalance, where the mice shifted their metabolism from fat to sugar. Researchers successfully reversed this condition with dietary adjustments that posed no risk to the animals.
Given these findings, the research team concluded that targeting macroH2A histone variants could be a safe and effective strategy for treating patients with AML. The results have prompted the establishment of a new research line at the Josep Carreras Institute, where scientists will further investigate macroH2A variants as potential drug targets for leukemia and other blood cancers.
As the research progresses, the implications for the future of AML treatment could be profound. With ongoing efforts to develop therapies that specifically target the molecular mechanisms of blood cancers, the work of Dr. Buschbeck and his colleagues represents a significant step toward more effective and safer treatment options for patients facing this challenging disease.
For further details, refer to the study by René Winkler et al, titled “Loss of histone macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization,” published in Science Advances in March 2025.
