Tyrosine kinase inhibitor induce CML migration to stromal microenvironment through Lyn/CXCR4 interactions in lipid rafts

p210 Bcr-Abl酪氨酸激酶抑制CXCR 4介导的慢性粒细胞白血病（CML）细胞向骨髓基质的迁移反过来，CML细胞暴露于酪氨酸激酶抑制剂（TKI）增强了CML细胞向基质细胞层的迁移，并促进了对伊马替尼的非药理学耐药性。已知Src相关激酶林恩与CXCL 12/CXCR 4信号传导相互作用，并被p210 Bcr-Abl直接激活。在与间充质基质细胞共培养下，TKI处理诱导CXCR 4定位在脂筏部分中，其进一步与CML细胞中的活性磷酸化形式的林恩（LynTyr 396）共定位。林恩抑制或胆固醇耗竭消除伊马替尼诱导的迁移。这些发现证明了脂筏通过多价CXCR 4和林恩复合物的隔室变化在伊马替尼诱导的CML迁移和在骨髓微环境中的寄宿中的关键作用。

p210Bcr-Abl tyrosine kinase inhibits CXCR4-mediated migration of chronic myeloid leukemia(CML) cells to bone marrow stroma. In turn, exposure of CML cells to a tyrosine kinase inhibitor(TKI) enhances migration of CML cells toward stromal cell layers and promotes nonpharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/CXCR4 signaling and is directly activated by p210Bcr-Abl. TKI treatment under co-culture with mesenchymal stromal cells induced CXCR4 localization in the lipid raft fraction, which further co-localized with active phosphorylated form of Lyn(LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration. These findings demonstrate the critical role of lipid rafts in imatinib-induced CML migration and lodging within the bone marrow microenvironment through the compartmental changes of the multivalent CXCR4 and Lyn complex.