Current prognostic scores in multiple myeloma (MM) currently rely on disease burden and a limited set of genomic alterations. Some studies have suggested gene expression panels may predict clinical outcomes, but none are presently utilized in clinical practice. The tyrosine kinase WEE1 is a critical cell cycle regulator during the S-phase and G2M checkpoint. Abnormal WEE1 expression has been implicated in multiple cancers including breast, ovarian, and gastric cancers, but its prognostic signal in MM has not been thoroughly reported. We, therefore, analyzed the MMRF CoMMpass dataset (N = 659) and identified a high-risk group (top tertile) and a low-risk group (bottom tertile) based on WEE1 expression sorted in descending order. PFS was significantly different (p < 1e-9) between the groups, which was validated in two independent microarray gene expression profiling (GEP) datasets from the Total Therapy 2 (N = 341) and 3 (N = 214) trials. Our results show that WEE1 expression is prognostic independent of known biomarkers, differentiates outcomes associated with known markers, is upregulated independently of its interacting neighbors, and is associated with dysregulated P53 pathways. This suggests that WEE1 expression levels may have clinical utility in prognosticating outcomes in newly diagnosed MM and may support the application of WEE1 inhibitors to MM preclinical models. Determining the causes of abnormal WEE1 expression may uncover novel therapeutic pathways.
目前多发性骨髓瘤（MM）的预后评分主要依赖疾病负荷和有限的基因组改变指标。部分研究提示基因表达谱可能预测临床结局，但尚未应用于临床实践。酪氨酸激酶WEE1是S期和G2/M检查点的关键细胞周期调节因子。异常WEE1表达与乳腺癌、卵巢癌、胃癌等多种癌症相关，但其在MM中的预后意义尚未被系统报道。为此，我们分析了MMRF CoMMpass数据集（N=659），基于WEE1表达降序排列划分出高危组（上三分位）和低危组（下三分位）。两组间无进展生存期差异显著（p<1e-9），该结果在Total Therapy 2（N=341）和Total Therapy 3（N=214）试验的两个独立微阵列基因表达谱数据集中得到验证。研究表明，WEE1表达的预后价值独立于已知生物标志物，能区分已知标志物的预后差异，其上调机制不依赖相互作用相邻基因，且与P53通路失调相关。这表明WEE1表达水平可能具有评估新诊断MM预后的临床应用价值，并为WEE1抑制剂在MM临床前模型中的应用提供依据。探究WEE1异常表达的原因可能揭示新的治疗路径。
High WEE1 expression is independently linked to poor survival in multiple myeloma
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