Abstract

The fusion gene of ABL1 is closely related to tumor proliferation, invasion, and migration. It has been reported recently that ABL1 itself is required for T-cell acute lymphoblastic leukemia (T-ALL) cell migration induced by CXCL12. Further experiments revealed that ABL1 inhibitor Nilotinib inhibited leukemia cell migration induced by CXCL12, indicating the possible application of Nilotinib in T-ALL leukemia treatment. However, the interacting proteins of ABL1 and the specific mechanisms of their involvement in this process need further investigation. In the present study, ABL1 interacting proteins were characterized and their roles in the process of leukemia cell migration induced by CXCL12 were investigated. Co-immunoprecipitation in combination with mass spectrometry analysis identified 333 proteins that interact with ABL1, including Cofilin1. Gene ontology analysis revealed that many of them were enriched in the intracellular organelle or cytoplasm, including nucleic acid binding components, transfectors, or co-transfectors. Kyoto Encyclopedia of Genes and Genomes analysis showed that the top three enriched pathways were translation, glycan biosynthesis, and metabolism, together with human diseases. ABL1 and Cofilin1 were in the same complex. Cofilin1 binds the SH3 domain of ABL1 directly; however, ABL1 is not required for the phosphorylation of Cofilin1. Molecular docking analysis shows that ABL1 interacts with Cofilin1 mainly through hydrogen bonds and ionic interaction between amino acid residues. The mobility of leukemic cells was significantly decreased by Cofilin1 siRNA. These results demonstrate that Cofilin1 is a novel ABL1 binding partner. Furthermore, Cofilin1 participates in the migration of leukemia cells induced by CXCL12. These data indicate that ABL1 and Cofilin1 are possible targets for T-ALL treatment.

中文翻译：

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ABL1 和 Cofilin1 促进 T 细胞急性淋巴细胞白血病细胞迁移

摘要

ABL1的融合基因与肿瘤的增殖、侵袭和迁移密切相关。最近有报道称，ABL1 本身是 CXCL12 诱导的 T 细胞急性淋巴细胞白血病 (T-ALL) 细胞迁移所必需的。进一步的实验表明，ABL1抑制剂尼罗替尼抑制了CXCL12诱导的白血病细胞迁移，表明尼罗替尼在T-ALL白血病治疗中的可能应用。然而，ABL1 的相互作用蛋白及其参与该过程的具体机制需要进一步研究。在本研究中，对 ABL1 相互作用蛋白进行了表征，并研究了它们在 CXCL12 诱导的白血病细胞迁移过程中的作用。共免疫沉淀结合质谱分析确定了 333 种与 ABL1 相互作用的蛋白质，包括 Cofilin1。基因本体分析表明，它们中的许多都富集在细胞内细胞器或细胞质中，包括核酸结合成分、转染子或共转染子。京都基因和基因组百科全书分析表明，前三个富集途径是翻译、聚糖生物合成和代谢，以及人类疾病。ABL1 和 Cofilin1 在同一个复合体中。Cofilin1 直接结合 ABL1 的 SH3 结构域；然而，ABL1 不是 Cofilin1 磷酸化所必需的。分子对接分析表明，ABL1 与 Cofilin1 的相互作用主要通过氨基酸残基间的氢键和离子相互作用。Cofilin1 siRNA 显着降低了白血病细胞的迁移率。这些结果表明 Cofilin1 是一种新的 ABL1 结合伙伴。此外，Cofilin1 参与 CXCL12 诱导的白血病细胞迁移。这些数据表明 ABL1 和 Cofilin1 是 T-ALL 治疗的可能目标。