Researchers Uncover Safe Target for Treating Acute Myeloid Leukemia

Scientists at the Josep Carreras Leukaemia Research Institute have discovered a safe new approach for targeting acute myeloid leukemia (AML) through the manipulation of specific histones. Researchers Dr. Marcus Buschbeck and Dr. René Winkler found that removing any of the three proteins from the macroH2A family of histones in mice did not adversely affect their health. This finding opens new therapeutic avenues for treating blood cancers, which often relapse and pose significant challenges for patients.

Acute myeloid leukemia is a particularly aggressive form of blood cancer that frequently eludes long-term control, necessitating the urgent development of novel treatments. The research team led by Dr. Buschbeck, who heads the Chromatin, Metabolism and Cell Fate lab at the institute, is focused on identifying druggable targets related to chromatin—the structure that houses genetic information and regulates gene expression. Their work emphasizes the role of histones, essential proteins that maintain chromatin structure and genome stability.

Historically, targeting histones for therapeutic purposes has been considered complex due to their critical role in cell survival, as any interference could result in severe side effects.

“This deprives us of the opportunity to develop new medicines against this important blood cancer driver mechanism,”

stated Ari Melnick, Director of the Josep Carreras Institute.

Despite past challenges, Dr. Buschbeck’s research has identified macroH2A histones as promising candidates for targeted therapy. Previous studies have linked these histones to acute myeloid leukemia, reinforcing the rationale for further investigation. In their latest experiments, published in the journal Science Advances, the research team explored the effects of removing each of the three macroH2A variants in healthy mice.

The experiments, led by Dr. Winkler and involving collaboration with experts from the Helmholtz Center Munich and the German Mouse Clinic, monitored over 500 parameters in mice to detect even the slightest effects of the treatment. Remarkably, the results indicated no significant adverse effects from the removal of macroH2A histones. The only notable finding was a mild kidney condition linked to the removal of the macroH2A1.1 variant, which arose from a metabolic shift from fat to sugar. Researchers were able to mitigate this condition through minor dietary adjustments, demonstrating that the treatment posed no significant risk to the animals.

The conclusion drawn by the research team is that targeting macroH2A histone variants could be a safe strategy for patients suffering from acute myeloid leukemia and potentially other blood cancers. This discovery has led to the establishment of a new research line at the Josep Carreras Leukaemia Research Institute, where researchers will broadly assess macroH2A variants as viable drug targets.

The potential for developing new therapeutic options is crucial, as blood cancers continue to challenge existing treatment protocols. With this innovative approach, the institute aims to pave the way for groundbreaking advancements in the fight against acute myeloid leukemia and similar conditions.

For further details, refer to the study: René Winkler et al, “Loss of histone macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization,” Science Advances (2025). DOI: 10.1126/sciadv.adz1242.