A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia.
A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia.
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急性髓系白血病(AML)被认为是由自我更新的白血病干细胞(LSCs)维持的。最近，来自功能定义的AML LSC群体的基因表达特征(GES)被报道，在细胞遗传学正常(CN)的AML中，表达代表LCSs中激活的44个基因的‘核心富集型’(CE)GES的表达使患者的生存时间缩短。CEGES在包括基因突变和microRNA(MiR)表达改变在内的其他分子标志物的背景下对预后的影响尚不清楚，其临床应用也不清楚。我们在364例特征良好的CN-AML患者中研究了CEGES与已知的分子预测因子、miR表达谱和预后的相关性。高CE评分(CEHigh)与Flt3-内部串联复制、WT1和RUNX1突变、野生型CEBPA和TET2以及高ERG、BAALC和miR-155表达相关。CEHigh患者的完全缓解率(CR)(P=0.003)、无病生存时间(DFS，P<；0.001)和总生存期(OS，P<；0.001)均低于CElow患者。这些关联持续存在于调整其他预测因素的多变量分析中(CR，P=0.02；DFS，P<；0.001；OS，P<；0.001)。CEHigh状态伴随着一个特征性的miR表达特征。15个MIR在年轻和老年CEHigh患者中均上调，其中包括与干细胞功能相关的MIR。我们的结果支持LSCs的临床相关性，并改善AML的风险分层。
Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a ‘core enriched’ (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CEhigh) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CEhigh patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CElow patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CEhigh status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CEhigh patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.
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