Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
Cancer Res. 2024 Jul 2;84(13):2090-2108. doi: 10.1158/0008-5472.CAN-23-2314.
Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.
急性髓系白血病（AML）是一种侵袭性和异质性血液恶性肿瘤。在老年患者中，AML 的发病率较高，由于缺乏有效的治疗方法，预后较差。G 蛋白偶联受体（GPCR）在生理过程和人类疾病中发挥着重要作用。特别是，粘附 GPCR 是 GPCR 中的第二大类，其中三分之一在造血干细胞和祖细胞或谱系细胞中高度表达。在这里，我们研究了粘附 GPCR 在 AML 中的作用以及它们是否可以被用作抗白血病靶点。通过生物信息学和功能分析系统地筛选粘附 GPCR 对 AML 功能的影响，发现 ADGRE2 在 AML 中高表达，特别是在白血病干细胞中，这与患者预后不良相关。沉默 ADGRE2 不仅在 AML 细胞系和来自 AML 患者的细胞中发挥抗白血病作用，而且在体内异种移植模型中也延迟 AML 进展。在机制上，ADGRE2 激活磷脂酶 Cβ/蛋白激酶 C/MEK/ERK 信号通路，增强 AP1 的表达，并转录驱动蛋白磷酸酶 DUSP1 的表达。DUSP1 去磷酸化共伴侣 DNAJB1 的 J 结构域中的 Ser16，促进 DNAJB1-HSP70 相互作用并维持 AML 中的蛋白质稳态。最后，联合抑制 MEK、AP1 和 DUSP1 在 AML 异种移植小鼠模型中显示出强大的治疗效果。总之，这项研究阐明了 ADGRE2 在 AML 中的作用和机制，并为治疗 AML 提供了有前途的治疗策略。意义：在 AML 中，粘附 GPCR 成员 ADGRE2 的表达增加，通过 MEK/AP1/DUSP1 轴调节蛋白质稳态，支持白血病干细胞自我更新和白血病发生，可作为抑制 AML 进展的靶点。
