PO.ET02.10 · 实验与分子治疗
WNK1抑制通过ERK-CEBPbeta信号诱导AML分化
WNK1 inhibition induces AML differentiation via ERK-CEBPbeta signaling
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
分化受损是急性髓系白血病（AML）的关键病理特征。诸如全反式维甲酸（ATRA）等AML分化诱导剂在治疗AML患者方面已显示出巨大前景，表现为总体生存和复发率的改善。然而，这一成功仅限于一部分AML患者，即急性早幼粒细胞白血病（APL）患者。这凸显了需要鉴定更多可能对其他AML亚型有效的分化治疗选择。在本研究中，我们鉴定出无赖氨酸(K)激酶1（WNK1）为AML分化停滞的新型调节因子。我们展示了AML患者中WNK1失调的证据，表现为其表达和活性相比健康对照升高。通过基因或药理学抑制靶向WNK1可在体外诱导AML细胞系的粒细胞分化。WNK1抑制还引起细胞周期停滞和凋亡。此外，口服WNK1抑制剂降低了AML异种移植模型中的白血病负荷。我们观察到敲低WNK1底物SPAK和OSR1的表达可模拟WNK1抑制的效应，提示它们参与介导WNK1的促白血病功能。在机制上，我们展示WNK1抑制通过促进MEK-ERK活性并增加C/EBPbeta活性和表达来诱导分化，从而增加髓系分化基因的转录。最后，我们说明将WNK1抑制与ATRA联合可进一步提升ATRA的疗效，协同增加分化、凋亡和细胞周期停滞。该联合治疗也增强了C/EBPbeta表达，提示C/EBPbeta在介导这些抗白血病效应中的作用。综上所述，我们的发现表明WNK1可能通过SPAK/OSR1负向调节ERK磷酸化和活性。抑制WNK1可解除对ERK的抑制，增加C/EBPbeta活性和表达，从而导致髓系分化。总体而言，我们的发现揭示了WNK1在促进分化停滞中的新作用，并凸显其作为AML治疗新靶点的潜力。
查看英文原文 English abstract
Impaired differentiation is a key pathological feature of Acute Myeloid Leukemia (AML). AML differentiation-inducing agents such as all-trans retinoic acid (ATRA) have shown great promise to treat AML patients as seen by improved overall survival and relapse rates. However, this success has been limited to a subset of AML patients, namely those with Acute Promyelocytic Leukemia (APL). This highlights the need to identify more differentiation therapy options that could be effective for other AML subtypes. In this study, we identified With-no-Lysine(K) kinase 1 (WNK1) as a novel regulator of AML differentiation arrest. We show evidence of WNK1 dysregulation in AML patients demonstrated by its increased expression and activity compared to healthy controls. Targeting WNK1 through genetic or pharmacologic inhibition induced granulocytic differentiation of AML cell lines in vitro. WNK1 inhibition also caused cell cycle arrest and apoptosis. Furthermore, oral administration of WNK1 inhibitor reduced leukemic burden in AML xenograft models. We observed that knocking down expression of WNK1 substrates SPAK and OSR1 mirrored the effects of WNK1 inhibition suggesting their involvement in mediating pro-leukemic functions of WNK1. Mechanistically, we show that WNK1 inhibition induces differentiation by promoting MEK-ERK activity and increasing C/EBPbeta activity and expression, resulting in increased transcription of myeloid differentiation genes. Finally, we illustrate that combining WNK1 inhibition with ATRA further boosts ATRA's efficacy, synergistically increasing differentiation, apoptosis, and cell cycle arrest. C/EBPbeta expression was also enhanced by this combination treatment, suggesting a role for C/EBPbeta in mediating these anti-leukemic effects. Taken together, our findings suggest that WNK1 negatively regulates ERK phosphorylation and activity, likely through SPAK/OSR1. Inhibiting WNK1 releases ERK suppression, increasing C/EBPbeta activity and expression which leads to myeloid differentiation. Overall, our findings reveal a novel role for WNK1 in promoting differentiation arrest and highlight its potential as a new therapeutic target for AML treatment.
利益披露 Disclosure
J. D. Cress, None..
E. Katoni, None..
P. Ramakrishnan, None.