[急性骨髄性白血病患者におけるIDH1およびIDH2変異の分析]

目的：IDH遺伝子（IDH1およびIDH2）変異の有病率、急性骨髄性白血病（AML）患者の変異の種類、FLT3遺伝子の内部タンデム重複（ITD）変異との相関、NPM1遺伝子変異、およびいくつかの臨床的特徴を探ること。 方法：Exon 4のIDH1およびIDH2遺伝子の変異、エクソン12のNPM1遺伝子、および163人の新たに診断されたAML患者のExon 14および15のFLT3-ITDの変異は、PCR増幅の後にゲノムDNAの直接配列決定によって検出されました。 結果：（1）IDH変異は25人の患者（25/163）で発見され、すべてがヘテロ接合であり、そのうち7人の患者（4.29％）、18人（11.04％）でIDH2がIDH1でした。合計4種類のIDH1変異が特定されました（C.395G→A、P.R132H、n = 4; C.394C→A、P.R132S、n = 1; C.394C→G、P.R132G、N n= 1; c.315c→t、n = 1）。IDH1変異は、1つ（C.315C→T）を除き、残基R132の置換を引き起こしました。すべてのIDH2変異により、R140（C.419G→A、P.R140Q、n = 18）の変化が発生しました。IDH2変異の発生率は、IDH1変異の発生率よりも有意に高かった（11.0％V 4.3％、P = 0.022）。IDH1とIDH2の両方の突然変異は、1人の患者で検出されましたが、IDH1は同義の置換（C.315C→T）でした。IDH変異症例は、野生型症例（34.6％対11.9％、P = 0.003）と比較して、同時FLT3-ITD変異の頻度が有意に高いことを示したため、IDH変異はNPM1変異とNPM1野生型（28.1％対12.7％、P = 12.7％を同時に示しました。0.033）は、同時NPM1およびFLT-ITD変異の頻度をIDH変異を伴う頻度は、NPM1およびFLT-ITD陰性の症例よりも有意に高かった（45.5％対11.7％、P = 0.002）。IDH変異の発生率は、異常なものよりも正常な核型の症例よりも有意に高かった（20.5％対5.8％、P = 0.020）。IDH変異の患者は野生型患者よりも有意に古かった（P <0.001）が、2つのグループ間の診断時に性別、末梢血（PB）カウントに統計的に有意な差はなかった。 結論：IDH変異の発生率は、De novo AMLSの患者でより高く、そのうちIDH2変異はより頻繁に、そして診断時の高齢、正常な核型に関連する患者。IDH変異は、NPM1およびFLT3-ITD変異と強い関連性があり、IDH変異が白血病形成に対する後者の遺伝子と相乗効果があることを示唆しています。

OBJECTIVE: To explore the prevalence of IDH gene (IDH1 and IDH2) mutations, types of mutations in patients with acute myeloid leukemia (AML), correlation with the internal tandem duplication(ITD) mutation of FLT3 gene, NPM1 gene mutation and some clinical characteristics. METHODS: The mutations of IDH1 and IDH2 gene at exon 4, NPM1 gene at exon 12 and FLT3-ITD at exon 14 and 15 in 163 newly diagnosed AML patients were detected by PCR amplification followed by direct sequencing of genomic DNA. RESULTS: (1) IDH mutations were found in 25 patients (25/163), and all were heterozygous, of which IDH1 in 7 patients (4.29%) and IDH2 in 18 (11.04%). A total of 4 types of IDH1 mutations were identified (c.395G→A, p.R132H, n = 4; c.394C→A, p.R132S, n = 1; c.394C→G, p.R132G, n = 1; c.315C→T, n = 1). The IDH1 mutation caused substitutions of residue R132 except for one (c.315C→T). All IDH2 mutations caused changes of R140 (c.419G→A, p.R140Q, n = 18). The incidence of IDH2 mutation was significantly higher than that of IDH1 mutation (11.0% v 4.3%, P = 0.022). Both IDH1 and IDH2 mutation were detected in one patient, while IDH1 was synonymous substitution (c.315C→T). IDH-mutated cases showed a significantly higher frequency of concurrent FLT3-ITD mutation compared with wildtype cases (34.6% vs 11.9%, P = 0.003), so did IDH mutations concurrent NPM1 mutation vs NPM1 wildtype (28.1% vs 12.7%, P = 0.033), of which the frequency of concurrent NPM1 and FLT-ITD mutations cases with the IDH mutation was significantly higher than that of NPM1 and FLT-ITD negative (45.5% vs 11.7%, P = 0.002). IDH mutation incidence was significantly higher in normal karyotype cases than in abnormal ones (20.5% vs 5.8%, P = 0.020). Patients with IDH mutations were significantly older than wildtype patients(P < 0.001), whereas, there were no statistically significant differences in gender, peripheral blood (PB) count at diagnosis between two groups. CONCLUSIONS: The incidence of IDH mutation is higher in patients with de novo AMLs, of which IDH2 mutation more frequently, and the patients associated with older age, normal karyotype at diagnosis. IDH mutation has a strong association with NPM1 and FLT3-ITD mutations, suggesting that IDH mutation has synergistic effect with the latter gene on leukemogenesis.