Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation

Abstract

Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genomewide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P ‫؍‬ .002), isolated monosomy 8 (P ‫؍‬ .043), NPM1 mutation (P < .001), and FrenchAmerican-British M1 subtype (P < .001), but inversely associated with French-AmericanBritish M4 subtype (P ‫؍‬ .030) and expression of HLA-DR, CD13, and CD14 (P ‫؍‬ .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during followups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution. (Blood. 2010;115(14): 2749-2754)

DNMT3A mutations in acute myeloid leukemia

“…Mutations in NPM1, IDH1, and IDH2 were not detected in these patients either, a finding that is consistent with data reported in other studies. 4,[27][28][29][30] The virtual exclusion of mutations in these four genes in patients with a favorable-risk profile is not random and may reflect the leukemogenic properties of the fusion proteins created by these chromosomal rearrangements. The PML-RARA fusion protein, which is created by t(15;17), physically interacts with DNMT3A, and AML-ETO, which is created by t(8;21), interacts with DNMT1; both fusion proteins alter the methylation of specific promoters.…”

A single-tube, sensitive multiplex method for screening of isocitrate dehydrogenase 1 (IDH1) mutations

“…1 Very recently, a series of reports about this mutation in AML have been published in a cluster of manuscripts. [1][2][3][4][5][6][7] As IDH1 mutation brings prognostic information in glioma and possibly AML, 4,[8][9] identification of IDH1 R132 mutations will bring increasing clinical relevance. Moreover, the mutation seems quite stable and may serve as a marker for monitoring minimal residual disease.…”

“…Moreover, the mutation seems quite stable and may serve as a marker for monitoring minimal residual disease. 1 Hence, a sensitive and simple method for detecting this mutation will be highly desirable. We here report a very sensitive, single-tube, multiplex polymerase chain reaction (PCR)-based method, which has been verified by direct sequencing method.…”

“…1 Such selection is based solely on availability of samples, without consideration of any other factors. Comparison of this multiplex PCR with direct sequencing revealed perfect concordance except for 1 patient whose IDH1 mutation was detected only by multiplex PCR but not by direct sequencing (FL91 in Figure 1C).…”

“…[1][2][3][4][5][6][7] Another upstream forward primer was used to generate a product as an internal control. Combination of these 7 forward primers and a common reverse primer ( Figure 1A) would generate a shorter mutant and a longer control product in any genomic DNA containing any type of R132 mutation, whereas only the longer product would be seen in samples without this mutation ( Figure 1B).…”