IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively.
We here analyzed the frequency and distribution pattern of DNMT3A and IDH mutations and their associations with other molecular markers in normal karyotype AML patients.
Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG.
Here we report that WT1, a sequence-specific transcription factor, is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia (AML).
Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%).
Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.<b>Significance:</b> AMLs with mutations in <i>TET2</i> or <i>IDH2</i> are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221.
The molecular subclassification was as follows: 34.6% patients (n = 136) with AML with the <i>NPM1</i> mutation, 10.7% (n = 42) with AML with mutated chromatin or RNA-splicing genes or both, 1.5% (n = 6) with AML with <i>TP53</i> mutations, 13.5% (n = 53) with AML with biallelic <i>CEBPA</i> mutations, 2.0% (n = 8) with AML with <i>IDH2-R1</i>72 mutations and no other class-defining lesion, 29.5% (n = 116) with AML with driver mutations but no detected class-defining lesion, 4.3% (n = 17) with AML with no detected driver mutation, and 3.8% (n = 15) patients with AML who met the criteria for ≥2 genomic subgroups.
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key events in the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma.
Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer, and chondrosarcoma patients.
As the genetic landscape of AML has been mapped, other attractive targets for therapy have been discovered, including C-KIT, IDH1 and IDH2, NPM1, and MEK.
For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions.
Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.
Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.
<b/> AG-221 or enasidenib is a first-in-class selective inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) with early demonstrated clinical efficacy in acute myeloid leukemia as a single agent, yet with persistence of mutant <i>IDH2</i> clones.