Genomic subtyping and therapeutic targeting of acute erythroleukemia
Genomic subtyping and therapeutic targeting of acute erythroleukemia
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DOI：
10.1038/s41588-019-0375-1
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发表时间：
2019-04-01
期刊：
影响因子：
30.8
通讯作者：
Mullighan, Charles G.
中科院分区：
文献类型：
--
作者：
Iacobucci, Ilaria;Wen, Ji;Mullighan, Charles G.
急性红系白血病（Acute erythroid leukemia， AEL）是一种遗传基础尚不清楚的高风险白血病，在骨髓异常增生和髓系白血病谱系中的诊断存在争议。我们比较了159例患有非AEL髓系疾病的儿童和成人AEL病例的基因组特征，并定义了5个具有不同转录谱的年龄相关亚组：成人，TP53突变；NPM1突变;KMT2A突变/重新安排;成人，DDX41突变；儿科，NUP98重新排列。基因组特征影响预后，NPM1突变和HOXB9过表达与良好预后相关，TP53、FLT3或RB1改变与不良生存率相关。45%的病例中存在可靶向的信号突变，包括ALK和NTRK1的复发突变，后者驱动红细胞白血病发生，对TRK抑制敏感。这种AEL的基因组图谱为这种疾病的准确诊断和风险分层提供了框架，并为在这种高风险白血病中测试靶向治疗提供了依据。
Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.