Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p = .028), M4/M5 subtype (p = .000), FLT3-ITD mutation (p = .034), MLL status (p = .007) and a higher risk stratification (p = .001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL-rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL-rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL-rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression.

中文翻译：

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MLL 重排急性髓系白血病中的异常 TRPM4 表达及其阻断通过 AKT/GLI1/细胞周期蛋白 D1 途径诱导细胞周期停滞。

瞬时受体电位 Melastatin 亚家族成员 4 (TRPM4) 已被证明在几种癌症中异常表达，但在急性白血病中很少报道。基于数据库挖掘和验证实验，我们目前的数据显示 TRPM4 在 AML 患者和具有 MLL 基因重排的细胞系中选择性过表达。我们分析了经过验证的 AML 患者队列中 TRPM4 表达与临床参数之间的相关性。TRPM4 表达增加与显着的白细胞增多 (p = .028)、M4/M5 亚型 (p = .000)、FLT3-ITD 突变 (p = .034)、MLL 状态 (p = .007) 和更高的风险分层相关(p = .001)。在 MLL 重排的白血病细胞中，siRNA 介导的 TRPM4 敲低会损害增殖并在 G0/G1 期阻止细胞周期。我们认为 TRPM4 可能通过调节 AKT/GLI1/Cyclin D1 通路参与 MLL 重排白血病的发病机制。发现转录因子 HOXA9 通过与其启动子结合来上调 TRPM4 的表达。总之，TRPM4 在 MLL 重排的 AML 中过表达，阻断 TRPM4 可能是高 TRPM4 表达的 AML 患者的替代治疗方法。