Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.
With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.
Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.
The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.
Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.
“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.
He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.
“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.
“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”
The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.
In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.
The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.
The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.
“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”
The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.
“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”
As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.
“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”
