GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations.

GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA-double mutations. To explore their impact on this favourable-risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA-double/FLT3-inernal tandem duplication-negative patients.

The prognostic significance of IDH2 mutations in AML depends on the location of the mutation.

We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2(R140) significantly correlated with nucleophosmin mutations (NPM1(MUT)), whereas IDH2(R172) cases generally lacked other molecular mutations. An IDH2(R140) mutation was an independent favorable prognostic factor for relapse (P = .004) and overall survival (P = .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD(WT)NPM1(MUT)IDH2(R140) patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). The presence of an IDH2(R172) mutation was associated with a significantly worse outcome than IDH2(R140), and relapse in FLT3/ITD(WT)NPM1(WT)IDH2(R172) patients was comparable with adverse-risk cytogenetics patients (76% and 72%, respectively).

The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status.

Mutations in the isocitrate dehydrogenase gene (IDH1) were recently described in patients with acute myeloid leukemia (AML). To investigate their prognostic significance we determined IDH1 status in 1333 young adult patients, excluding acute promyelocytic leukemia, treated in the United Kingdom MRC AML10 and 12 trials. A mutation was detected in 107 patients (8%). Most IDH1(+) patients (91%) had intermediate-risk cytogenetics. Mutations correlated significantly with an NPM1 mutation (P < .0001) but not a FLT3/ITD (P = .9). No difference in outcome between IDH1(+) and IDH1(-) patients was found in univariate or multivariate analysis, or if the results were stratified by NPM1 mutation status. However, when stratified by FLT3/ITD status, an IDH1 mutation was an independent adverse factor for relapse in FLT3/ITD(-) patients (P = .008) and a favorable factor in FLT3/ITD(+) patients (P = .02). These results suggest that metabolic changes induced by an IDH1 mutation may influence chemoresistance in a manner that is context-dependent.

Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.

Ollier disease and Maffucci syndrome are characterized by multiple central cartilaginous tumors that are accompanied by soft tissue hemangiomas in Maffucci syndrome. We show that in 37 of 40 individuals with these syndromes, at least one tumor has a mutation in isocitrate dehydrogenase 1 (IDH1) or in IDH2, 65% of which result in a R132C substitution in the protein. In 18 of 19 individuals with more than one tumor analyzed, all tumors from a given individual shared the same IDH1 mutation affecting Arg132. In 2 of 12 subjects, a low level of mutated DNA was identified in non-neoplastic tissue. The levels of the metabolite 2HG were measured in a series of central cartilaginous and vascular tumors, including samples from syndromic and nonsyndromic subjects, and these levels correlated strongly with the presence of IDH1 mutations. The findings are compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in individuals with these syndromes.

Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations.

PURPOSE: To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact. PATIENTS AND METHODS: The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing. RESULTS: Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA-wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively). CONCLUSION: Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.