Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.
Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.
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DOI：
10.1038/leu.2016.332
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发表时间：
2017-06
期刊：
影响因子：
11.4
通讯作者：
Bloomfield CD
中科院分区：
文献类型：
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作者：
Eisfeld AK;Kohlschmidt J;Schwind S;Nicolet D;Blachly JS;Orwick S;Shah C;Bainazar M;Kroll KW;Walker CJ;Carroll AJ;Powell BL;Stone RM;Kolitz JE;Baer MR;de la Chapelle A;Mrózek K;Byrd JC;Bloomfield CD
核心结合因子急性髓性白血病（CBF-AML）定义为存在t（8;21）（q22;q22）/RUNX 1-RUNX 1 T1或inv（16）（p13.1q22）/t（16;16）（p13.1;q22）/CBFB-MYH 11。由此产生的融合基因需要“第二次打击”来启动白血病发生。177例CBF-AML成人患者（包括68例t（8;21）和109例inv（16）/t（16;16））的突变评估不仅确定了CBF-AML中已知的突变，还确定了CCND 1和CCND 2基因的突变，这代表了t（8;21）AML中新的频繁分子改变。在我们的队列中，在10例（15%）t（8;21）患者中检测到CCND 1（n=2）和CCND 2（n=8）突变。在1例（0.9%）inv患者中也发现了单个CCND 2突变（16）。相比之下，在1，426名非CBF-AML患者中仅检测到11名（0.77%）CCND 1和CCND 2突变。所有CCND 2突变都聚集在高度保守的氨基酸残基苏氨酸280（Thr 280）周围。我们发现，Thr 280 Ala突变的CCND 2导致视网膜母细胞瘤蛋白磷酸化增加，从而导致显著的细胞周期变化和AML细胞系增殖增加。CCND 1和CCND 2突变作为t（8;21）AML中常见的突变事件的鉴定可能为这种疾病的细胞周期导向治疗提供进一步的理由。
Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a “second hit” to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well-known in CBF-AML, but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1 (n=2) and CCND2 (n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2 mutation was also found in one (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1,426 non-CBF-AML patients. All CCND2 mutations cluster around the highly conserved amino acid residue threonine 280 (Thr280). We show that Thr280Ala mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1 and CCND2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.