Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia
Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia
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DOI：
10.1182/blood-2012-01-406116
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发表时间：
2012-05-31
期刊：
影响因子：
20.3
通讯作者：
Touw, Ivo P.
中科院分区：
文献类型：
--
作者：
Beekman, Renee;Valkhof, Marijke G.;Touw, Ivo P.
严重先天性中性粒细胞减少症 (SCN) 是一种骨髓衰竭综合征，极有可能进展为急性髓系白血病 (AML)。 SCN 进化为 AML 所涉及的潜在遗传变化在很大程度上尚不清楚。我们从一名 SCN 患者那里获得了系列造血样本，该患者在开始 G-CSF 治疗 17 年后出现了 AML。进行下一代测序来识别疾病进展过程中的突变。在 AML 阶段，我们发现了 12 个获得性非同义突变。其中 CSF3R、LLGL2 和 ZC3H18 中的三种在已经处于早期 SCN 阶段的祖细胞亚群中同时发生。该群体随着时间的推移而扩大，而仅携带 CSF3R 突变的克隆从 BM 中消失。其他 9 个突变仅在 AML 细胞中明显，并影响已知的 AML 相关基因（RUNX1 和 ASXL1）和染色质重塑基因（SUZ12 和 EP300）。此外，还发现了一种新的 CSF3R 突变，该突变赋予骨髓祖细胞自主增殖能力。我们得出的结论是，从 SCN 到 AML 的进展是一个多步骤的过程，在 SCN 阶段早期出现不同的突变，而在 AML 发展后期出现其他突变。 2 个 CSF3R 突变的连续增加表明异常的 G-CSF 信号传导是本例 SCN 白血病转化的驱动因素。 （血。2012；119（22）：5071-5077）
Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next-generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN. (Blood. 2012; 119(22): 5071-5077)