ABL SH3 mutant inhibits BCR-ABL activity and increases imatinib sensitivity by targeting RIN1 protein in CML cell. Issue 1 (1st December 2015)

• Record Type: Journal Article
• Authors: Liu, Xin; Li, Yajuan; Wen, Liangxue; Tao, Kun; Xiao, Qing; Cao, Weixi; Huang, Zhenglan; Gao, Miao; Li, Hui; Wang, Fang; Feng, Wenli
• Is Part Of: Cancer letters. Volume 369:Issue 1(2016)
• Page Start: 222
• Page End: 228
• Publication Date: 2015-12-01
• Subjects: Chronic myeloid leukemia -- BCR-ABL -- SH3 domain -- RIN1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.08.017
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Targeting the interaction of RIN1 and ABL using the ABL SH3 mutant T79Y significantly suppresses leukemia cell growth in vitro . ABL SH3 mutant T79Y markedly repressed the expression of BCR-ABL signaling pathways. Combination of ABL SH3 mutant T79Y potentiates the efficacy of IM in vitro and in vivo . Abstract: 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.