BCR-ABL is a constitutively active tyrosine kinase that stimulates multiple downstream signaling pathways to promote the survival and proliferation of chronic myeloid leukemia (CML) cells. The clinical application of specific BCR-ABL tyrosine kinase inhibitors (TKIs) has led to significantly improved prognosis and overall survival in CML patients compared to previous treatment regimens. However, direct targeting of BCR-ABL does not eradicate CML cells expressing T315I-mutated BCR-ABL. Our previous study revealed that inhibiting CREB binding protein (CBP) is efficacious in activating β-catenin/p300 signaling, promoting cell differentiation and inducing p53/p21-dependent senescence regardless of BCR-ABL mutation status. We hypothesize that the specific inhibition of CBP may represent a novel strategy to promote β-catenin/p300-mediated differentiation and suppress cancer cell proliferation for treating CML patients. The anticancer efficacy of PBA2, a novel CBP inhibitor, in CML cells expressing wild-type or T315I-mutated BCR-ABL was investigated in vitro and in vivo. Cell differentiation was determined by the nitroblue tetrazolium (NBT) reduction assay. The extent of cellular senescence was assessed by senescence-associated β-galactosidase (SA-β-Gal) activity. Cytotoxicity was measured by MTS assay. RNA interference was performed to evaluate the cell proliferation effects of CBP knockdown. The interaction of β-catenin and CBP/p300 was examined by co-immunoprecipitation assay. PBA2 exhibited significantly higher anticancer effects than imatinib in CML cells harboring either wild-type or T315I-mutated BCR-ABL both in vitro and in vivo. Mechanistically, PBA2 reduced CBP expression and promoted β-catenin-p300 interaction to induce cell differentiation and senescence. Our data supported the rational treatment of CML by inhibiting the β-catenin/CBP pathway regardless of BCR-ABL mutation status.

中文翻译：

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PBA2 是一种新型 β-连环蛋白/CBP 通路抑制剂，可根除包括 BCR-ABL T315I 突变在内的慢性粒细胞白血病


BCR-ABL 是一种组成型活性酪氨酸激酶，可刺激多个下游信号通路，促进慢性粒细胞白血病 (CML) 细胞的存活和增殖。与之前的治疗方案相比，特异性 BCR-ABL 酪氨酸激酶抑制剂 (TKI) 的临床应用显着改善了 CML 患者的预后和总生存率。然而，直接靶向 BCR-ABL 并不能根除表达 T315I 突变的 BCR-ABL 的 CML 细胞。我们之前的研究表明，无论 BCR-ABL 突变状态如何，抑制 CREB ​​结合蛋白 (CBP) 都能有效激活 β-catenin/p300 信号传导、促进细胞分化和诱导 p53/p21 依赖性衰老。我们推测，CBP 的特异性抑制可能代表了一种促进 β-catenin/p300 介导的分化并抑制癌细胞增殖的新策略，用于治疗 CML 患者。体外和体内研究了新型 CBP 抑制剂 PBA2 在表达野生型或 T315I 突变 BCR-ABL 的 CML 细胞中的抗癌功效。通过硝基蓝四唑 (NBT) 还原测定法测定细胞分化。通过衰老相关的 β-半乳糖苷酶 (SA-β-Gal) 活性来评估细胞衰老的程度。通过MTS测定来测量细胞毒性。进行RNA干扰以评估CBP敲除对细胞增殖的影响。通过免疫共沉淀测定检测 β-连环蛋白和 CBP/p300 的相互作用。在体外和体内，PBA2 在含有野生型或 T315I 突变 BCR-ABL 的 CML 细胞中表现出明显高于伊马替尼的抗癌效果。从机制上讲，PBA2 降低 CBP 表达并促进 β-catenin-p300 相互作用，从而诱导细胞分化和衰老。 我们的数据支持通过抑制 β-连环蛋白/CBP 通路来合理治疗 CML，无论 BCR-ABL 突变状态如何。