Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Doctoral Degree Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.
BMC Cancer. 2019 Jun 24;19(1):617. doi: 10.1186/s12885-019-5822-y.
Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS.
shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance.
Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P < 0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group.
This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.
长链非编码 RNA（lncRNA）代表了细胞转录本的大部分，在造血过程中发挥关键作用。然而，它们在急性髓系白血病（AML）和骨髓增生异常综合征（MDS）中的临床相关性仍知之甚少。在这里，我们研究了位于人类 HOXB 簇的 lncRNA HOXB-AS3 在髓系细胞中的功能，并分析了其在 AML 和 MDS 患者中的预后意义。
使用 shRNA 下调细胞系中的 HOXB-AS3，并通过定量聚合酶链反应评估其效果。通过增殖和 BrdU 流式细胞术来阐明细胞系的增殖情况。此外，我们通过微阵列分析对 193 例 AML 患者和 157 例 MDS 患者进行了 HOXB-AS3 表达的回顾性分析，并评估了其临床重要性。
下调 HOXB-AS3 抑制了细胞增殖。在机制上，HOXB-AS3 增强了细胞周期进展和 DNA 复制中几个关键因子的表达，而不影响 HOX 基因的表达。在 AML 中，HOXB-AS3 表达较高的患者的总生存期（OS）（中位数 OS，17.7 个月与未达到，P < 0.0001；中位无复发生存期，12.9 个月与未达到，P = 0.0070）短于 HOXB-AS3 表达较低的患者。在 MDS 中，HOXB-AS3 表达较高的患者的预后也不如 HOXB-AS3 表达较低的患者（中位数 OS，14.6 个月与 42.4 个月，P = 0.0018）。在 TCGA AML 队列和我们研究所的另一个 MDS 队列中验证了 HOXB-AS3 表达的预后意义。在 MDS 患者的亚组分析中，HOXB-AS3 表达较高仅在低危组（中位数 OS，29.2 个月与 77.3 个月，P = 0.0194），而不是高危组中可以预测不良预后。
本研究揭示了 HOXB-AS3 在髓系恶性肿瘤中的促进作用，并确定了 HOXB-AS3 表达在 AML 和 MDS 患者中的预后价值，特别是在低危组。
