The FABD domain is critical for the oncogenicity of BCR/ABL in chronic myeloid leukaemia

作者全名：Zheng, Renren; Wei, Wei; Liu, Suotian; Zeng, Dachuan; Yang, Zesong; Tang, Jie; Tan, Jinfeng; Huang, Zhenglan; Gao, Miao

作者地址：[Zheng, Renren; Wei, Wei; Liu, Suotian; Tang, Jie; Tan, Jinfeng; Huang, Zhenglan] Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost,Minist Educ, Chongqing, Peoples R China; [Zeng, Dachuan] Chongqing Med Univ, Dept Clin Lab, Women & Childrens Hosp, Chongqing, Peoples R China; [Zeng, Dachuan] Chongqing Hlth Ctr Women & Children, Dept Clin Lab, Chongqing, Peoples R China; [Yang, Zesong] Chongqing Med Univ, Affiliated Hosp 1, Dept Hematol, Chongqing, Peoples R China; [Gao, Miao] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing, Peoples R China

通信作者：Huang, ZL (通讯作者)，Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost,Minist Educ, Chongqing, Peoples R China.; Gao, M (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing, Peoples R China.

来源：CELL COMMUNICATION AND SIGNALING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001246064100003

JCR分区：Q1

影响因子：8.2

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：F-actin binding domain; BCR/ABL; Chronic myeloid leukaemia; Oncogenicity; p73

摘要：Background Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain.Methods The FABD-deficient adenovirus vectors Ad-BCR/ABL triangle FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright-Giemsa staining and haematoxylin and eosin (HE) staining.Results We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice.Conclusions These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL.

基金机构：Natural Science Foundation of Chongqing, China

基金资助正文：Not applicable.