An IDH2 mutation is a genetic alteration affecting the isocitrate dehydrogenase 2 enzyme. This alteration can disrupt normal cellular processes, leading to the production of an abnormal substance. These mutations are relevant in certain diseases, influencing cell behavior and development. Understanding this modification is important for diagnosis and targeted therapies.
What is IDH2 and How It Mutates
The IDH2 enzyme is normally located in the mitochondria, which generate energy for the cell. In its regular function, IDH2 plays a role in the Krebs cycle (also known as the TCA cycle), a series of chemical reactions that convert nutrients into energy. Specifically, IDH2 catalyzes the conversion of isocitrate into alpha-ketoglutarate (α-KG), a molecule important for energy production and gene regulation.
An IDH2 mutation occurs when a change happens in the IDH2 gene, typically at the Arg172 codon. This alters the enzyme’s normal function, giving it an abnormal activity. Instead of producing α-KG, the mutated IDH2 enzyme converts α-KG into an abnormal metabolite called 2-hydroxyglutarate (2-HG). High levels of 2-HG disrupt normal cell functions, affecting gene expression and cellular differentiation.
The IDH2 Mutation and Its Role in Disease
The IDH2 mutation is frequently associated with certain types of cancer, particularly acute myeloid leukemia (AML). In AML, the mutated IDH2 enzyme leads to an overproduction of 2-HG, which interferes with the ability of blood-producing cells in the bone marrow to mature properly. This disruption in cell differentiation results in an accumulation of immature, cancerous blood cells, a hallmark of AML.
IDH2 mutations are also found in other conditions, including gliomas (a type of brain tumor), primary myelofibrosis, and rare genetic disorders like Maffucci syndrome and Ollier disease. In gliomas, the abnormal production of 2-hydroxyglutarate due to the IDH2 mutation contributes to tumor formation by blocking cell maturation. The presence of an IDH2 mutation in these diseases can influence the disease’s course and how it responds to treatment, often being associated with a better prognosis in certain cancers.
Identifying IDH2 Mutations
Detecting IDH2 mutations is important for diagnosing certain cancers and guiding treatment decisions. Genetic testing methods identify these alterations in a patient’s DNA. Techniques such as next-generation sequencing (NGS) or polymerase chain reaction (PCR) pinpoint the change in the IDH2 gene.
Molecular detection is important. Identifying an IDH2 mutation confirms this genetic alteration, classifying a patient’s disease into a distinct molecular subtype. Knowing the mutational status allows clinicians to tailor treatment plans, as specific therapies target cells with IDH2 mutations. This precision helps personalize patient care and improve treatment outcomes.
Targeted Treatments for IDH2 Mutations
The discovery of IDH2 mutations led to targeted therapies that address the altered enzyme function. These medications, known as IDH2 inhibitors, block the activity of the mutated IDH2 enzyme. By inhibiting the abnormal conversion of alpha-ketoglutarate to 2-HG, these drugs reduce the levels of this harmful metabolite.
Enasidenib is an IDH2 inhibitor approved for patients with relapsed or refractory acute myeloid leukemia. Olutasidenib also targets the mutated IDH2 enzyme. These inhibitors help restore normal cellular differentiation and reduce uncontrolled proliferation of malignant cells, impacting disease progression and offering a precise treatment approach for patients with IDH2-mutated cancers.