Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia.
Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia.
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急性淋巴细胞白血病（ALL）的耐药性仍然是阻碍新的治疗策略的主要问题。Wnt/catenin信号传导对于正常造血祖细胞的自我更新至关重要。Wnt信号失调在慢性和急性髓性白血病中很明显，但对ALL知之甚少。连环蛋白与Kat 3共激活因子CREBBP（CBP）或高度同源的EP 300（p300）的差异相互作用对于确定不同的细胞反应至关重要，并为Wnt信号通路调节增殖和分化提供了理论基础。连环蛋白使用共激活因子CBP导致参与祖细胞自我更新维持的基因盒的转录激活。然而，辅激活因子p300的使用导致参与分化起始的基因的激活。ICG-001是Wnt/连环蛋白信号传导的新型小分子调节剂，其在氨基酸1-110内特异性结合CBP的N-末端而不是p300，从而破坏CBP和连环蛋白之间的相互作用。在这里，我们报告了使用ICG-001选择性破坏CBP/β-和γ-连环蛋白相互作用导致前B ALL细胞分化和自我更新能力丧失。在用ICG-001治疗后，原发性ALL中凋亡相关蛋白Survivin也下调。使用ChIP测定，我们证明了CBP对生存素启动子的占用，其在原发性ALL中被ICG-001降低。最近在相当大比例的ALL患者中发现了CBP突变，然而，几乎所有报告的已发现突变都发生在ICG-001结合位点的C末端。重要的是，无论CBP突变状态和染色体畸变如何，ICG-001在体外联合常规治疗均可根除耐药原发性白血病，并显著延长移植原发性ALL的NOD/SCID小鼠的生存期。因此，特异性抑制CBP/连环蛋白转录代表了克服ALL复发的新方法。
Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300, leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using ChIP assay, we demonstrate occupancy by CBP of the survivin promoter, which is decreased by ICG-001 in primary ALL. CBP-mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
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