In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies.
In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML.
In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024).
In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments.
In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.<i>See related commentary by Horton and Huntly, p. 699</i>.<i>This article is highlighted in the In This Issue feature, p. 681</i>.
In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum.
Indeed, in addition to the IDH1/2-mutated AML model which established the proof-of-concept for specifically targeting metabolic adaptations in AML, several recent reports have expanded the scope of such strategies in these diseases.
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.
Molecular evaluation of DNMT3A and IDH1/2 gene mutation: frequency, distribution pattern and associations with additional molecular markers in normal karyotype Indian acute myeloid leukemia patients.
Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML.
Mutation Analysis of Isocitrate Dehydrogenase (IDH1/2) and DNA Methyltransferase 3A (DNMT3A) in Thai Patients with Newly Diagnosed Acute Myeloid Leukemia
Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG).
Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature.
Mutations at arginine 132 of isocitrate dehydrogenase 1/2 (IDH1/2) have recently been demonstrated to be recurrent gene alterations in acute myeloid leukemia (AML).
Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with acute myeloid leukemia (AML) and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate (R-2-HG).
Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in most grade 2 and 3 gliomas, secondary glioblastomas, and a subset of acute myelogenous leukemias but have not been detected in other tumor types.
Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases.