ABL SH3 mutant inhibits BCR-ABL activity and increases imatinib sensitivity by targeting RIN1 protein in CML cell

作者：Liu Xin; Li Yajuan; Wen Liangxue; Tao Kun; Xiao Qing; Cao Weixi; Huang Zhenglan; Gao Miao; Li Hui; Wang Fang; Feng Wenli^*

来源：Cancer Letters, 2015, 369(1): 222-228.

DOI：10.1016/j.canlet.2015.08.017

• Chronic myeloid leukemia
• BCR-ABL
• SH3 domain
• RIN1

SH3 domain plays an important role in maintaining autoinhibition of BCR-ABL protein. RIN1 interacts with BCR-ABL SH3 domain via PxxP motifs to promote autophosphorylation as well as activation of BCR-ABL tyrosine kinase, suggesting using exogenous SH3 domain which blocks the interaction of BCR-ABL and RIN1 could be an adjunct therapy for CML. Here, we reported a novel p-BCR-ABL inhibitor, designed as ABL SH3 mutant, and identified its effects on inhibiting the tyrosine kinase activity of BCR-ABL without or with imatinib (IM) in vitro and in vivo. Our results demonstrated that ABL SH3 mutant T79Y markedly repressed the expression of BCR-ABL signaling pathways in IM-resistant cell lines KCL22 and K562/G01 as well as IM-sensitive cell line K562. Moreover, combination of T79Y with IM considerably decreased the proliferation of leukemia cells in vivo. Inhibition of BCR-ABL and RIN1 interaction using exogenous modified BCR-ABL SH3 domain provides a feasible and alternative option of small molecule inhibitors for CML treatment.

• 出版日期2015-12-1
• 单位重庆医科大学