Even though targeted therapies are often efficacious in acute myeloid leukemia (AML), treatment resistance is sometimes inevitable. Mutations in isocitrate dehydrogenase (IDH) enzymes occur in approximately 20% of AML cases and could be a potential factor in treatment resistance. In order to produce a more effective therapy, researchers tracked the evolution of leukemia from mutant IDH2 dependence to independence and found two vulnerabilities of IDH2-mutant leukemia that can serve as potential therapeutic targets.
"There is an acute need to develop rational combinations to treat disease and overcome resistance that arises in response to therapy," commented one of the study authors, Pier Paolo Pandolfi, MD, PhD, George C. Reisman Professor of Medicine and Professor of Pathology and Medicine at Harvard Medical School. "By providing a critical understanding of the mechanisms underlying the disease, we identified a therapeutic strategy for treatment of this type of AML."
In this study, published in Cell Research, the scientists categorized IDH2-mutant leukemia by oxidative and genotoxic stress, in spite of increased levels of glutathione and 1-carbon metabolism, which is involved in synthesizing molecules that are incorporated into DNA or synthesizing purines, the building blocks of DNA.
IDH2-mutant leukemia hinders lysine-specific demethylase 1 (LSD1), which results in hinderance of a transcriptional signature of all-trans retinoic acid (ATRA) sensitization. Using this information, the investigators discovered that glutathione/reactive oxygen species (GSH/ROS) and poly1 isomerase (PIN1)/LSD1 are crucial to leukemia maintenance.
The researchers found that the combination of ATRA and arsenic trioxide was effective in targeting these vulnerabilities in both human and mouse models of IDH1/2-mutant AML.
The study authors conclude, "Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted acute promyelocytic leukemia (APL)-like combinatorial therapies."
For More Information
Mugoni V, Panella R, Cheloni G, et al (2019). Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. Cell Res. [Epub ahead of print] DOI:10.1038/s41422-019-0162-7
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