Abstract
ObjectiveMutations in the gene encoding isocitrate dehydrogenease 1 (IDH1) occur in various hematopoietic tumors including acute myeloid leukemia (AML), myeloproliferative neoplasms and myelodysplastic syndromes. IDH1 mutations are significant in both diagnosis and prognosis of these conditions. In the present study we determined the prevalence and clinical significance of IDH1 mutations in 349 samples from newly diagnosed AML patients.ResultsOf the 349 AML patient specimens analyzed, 35 (10.03%) were found to have IDH1 mutations including 4 IDH1 R132 mutations and 31 non-R132 mutations. IDH1 non-R132 mutations were largely concentrated within AML-M1 (35.72%, p<0.01). We identified five IDH1 mutations that were novel to AML: (1) c.299 G>A, p.R100Q; (2) c.311G>T, p.G104V; (3) c.322T>C, p.F108L; (4) c.356G>A, p.R119Q; and (5) c.388A>G, p.I130V. In addition, we identified three IDH1 mutations that were previously described in AML. The frequency of IDH1 mutations in AML patients with normal karyotype was 9.9%. IDH1 non-R132 mutations were concurrent with mutations in FLT3-ITD (p<0.01), CEBPA (p<0.01), and NRAS (p<0.01), as well as the overexpression of MN1 (p<0.01) and WT1(p<0.01). The overall survival (OS) in the patients with IDH1 non-R132 mutations compared to patients without IDH1 mutations don't reach statistically significance (median 521 days vs median: not reached; n.s.).Conclusion IDH1 non-R132 mutations occurred frequently in newly diagnosed adult Chinese AML patients, and these mutations were associated with genetic alterations. The OS was not influenced by IDH1 non-R132 mutations in the present study.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by mutations in clonal multipotent stem cells or early myeloid progenitor cells
Clinical features of AML patients with isocitrate dehydrogenease 1 (IDH1) mutations Of the 349 newly diagnosed adult Chinese AML patients, 35 patients (10.03%) had IDH1 mutations, including 4 IDH1 R132 mutation patients and 31 IDH1 non-R132 mutation patients
I99M is not a substrate binding site, it is in close proximity to R100 and the substrate biding region, which supports the notion that it may play a role in AML pathogenesis
Summary
Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by mutations in clonal multipotent stem cells or early myeloid progenitor cells. This disease is extremely diverse with regards to clinical manifestation, prognosis and outcome. Some AML patients lack distinctive chromosomal abnormalities, molecular biological studies have demonstrated that certain genetic mutations and abnormalities in gene expression are related to AML prognosis. The IDH1 gene is located on chromosome 2 at 2q33.3. Mutations in IDH1 impairs the affinity of the enzyme for its substrate, thereby inhibiting its enzymatic activity leading to decreased formation of a-KG and increased HG production
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