伊马替尼耐药仍然是 CML 疾病中尚未解决的问题。 JAK2/STAT3通路的激活和RUNX1表达的增加已成为CML受试者产生伊马替尼耐药的原因之一。近年来，二甲双胍作为抗白血病药物受到关注。然而，其分子机制仍然难以捉摸。本研究表明，RUNX1 是 AMP 激活激酶 (AMPK) 的新型底物，其中 AMPK 在 Ser 94 位点磷酸化 RUNX1。二甲双胍激活 AMPK 可能会由于 Ser 94 磷酸化而导致 RUNX1 的细胞质保留增加。 RUNX1 Ser 94 磷酸化导致与 STAT3 的相互作用增加，这反映在 RUNX1 和 STAT3 由于细胞质滞留而导致转录活性降低。 STAT3 和 RUNX1 转录活性的降低导致其参与增殖和抗凋亡的信号靶标下调。我们使用体外耐药细胞系模型和从 CML 临床患者和正常受试者中分离的 PBMC 进行的细胞增殖测定表明，二甲双胍治疗导致耐药受试者生长减少并提高伊马替尼敏感性。© 2023。作者。

Imatinib resistance remains an unresolved problem in CML disease. Activation of JAK2/STAT3 pathway and increased expression of RUNX1 have become one reason for development of imatinib resistance in CML subjects. Metformin has gained attention as an antileukemic drug in recent times. However, the molecular mechanism remains elusive. The present study shows that RUNX1 is a novel substrate of AMP-activated kinase (AMPK), where AMPK phosphorylates RUNX1 at Ser 94 position. Activation of AMPK by metformin could lead to increased cytoplasmic retention of RUNX1 due to Ser 94 phosphorylation. RUNX1 Ser 94 phosphorylation resulted in increased interaction with STAT3, which was reflected in reduced transcriptional activity of both RUNX1 and STAT3 due to their cytoplasmic retention. The reduced transcriptional activity of STAT3 and RUNX1 resulted in the down-regulation of their signaling targets involved in proliferation and anti-apoptosis. Our cell proliferation assays using in vitro resistant cell line models and PBMCs isolated from CML clinical patients and normal subjects demonstrate that metformin treatment resulted in reduced growth and improved imatinib sensitivity of resistant subjects.© 2023. The Author(s).