Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication
Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication
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DOI：
10.1182/bloodadvances.2020002673
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发表时间：
2020-12-22
期刊：
影响因子：
7.5
通讯作者：
Bullinger, Lars
中科院分区：
文献类型：
--
作者：
Jahn, Nikolaus;Terzer, Tobias;Bullinger, Lars
核心结合因子（CBF）急性髓系白血病（AML）包括AML with inv(16)（p13.1q22）和AML with t(8;21)（q22;q22.1）。尽管具有共同的致病机制，涉及CBF转录复合体的重排，但越来越多的证据表明存在相当大的基因型异质性。我们全面表征了350例成人CBF-AML的突变景观[v(16): n = 160, t(8;21): n = 190]，对230个髓系癌相关基因进行了靶向测序。除了信号基因（主要是NRAS、KIT和FLT3）的常见突变外，两种CBF-AML实体在潜在的协同分子事件方面表现出显著不同的模式，特别是在编码表观遗传修饰因子和内聚蛋白复合物的基因方面。此外，还发现了新的协同候选基因如SRCAP（总体5%）和DNM2 （t(8;21) AML的6%）的复发性突变。此外，改变转录和分化的畸变发生在早期白血病阶段，并先于损害增殖的突变。套索惩罚模型显示，t(8;21) AML、8三体、FLT3和KIT外显子17突变的预后较差，而NRAS和WT1突变的预后较好。有趣的是，克隆异质性与良好的预后相关。在模型中按功能组进入突变时，甲基化组基因（即DNMT3A、TET2）的突变对预后有很强的负面影响。
Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.