KEY TAKEAWAYS
- The study aimed to identify the precise function of the FABD in the BCR/ABL fusion protein, having a pivotal role in the development of CML.
- Researchers noticed that the FABD deletion reduced BCR/ABL carcinogenic potential, revealing its crucial role in CML.
Abnormally expressed BCR/ABL protein forms a firm 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.
Renren Zheng and the team aimed to elucidate the precise function of the FABD in the BCR/ABL fusion protein, which plays a crucial role in the development of CML.
Researchers constructed the FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL, and the control vector Adtrack, and infected 32D cells with these adenoviruses distinctively. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were assessed by a CCK-8 assay, colony formation assay, flow cytometry, and DAPI staining.
The Western blotting method was employed to detect the levels of phosphorylated BCR/ABL, p73, and their downstream signaling molecules. Further, immunofluorescence and co-IP identified the intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin.
The FABD deletion influenced the BCR/ABL expression and induced carcinogenesis, which was investigated using CML- like models. Leukemic cell infiltration was assessed through Wright-Giemsa staining and hematoxylin and eosin (HE) staining.
They reported that the loss of FABD reduced the proliferation-promoting ability of BCR/ABL, along with the downregulation of signals downstream to BCR/ABL. Moreover, FABD deletion consequently altered the localization of BCR/ABL from the cytoplasm to the nucleus, which subsequently led to enhanced cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Additionally, they discovered that the absence of FABD alleviated leukemic cell infiltration which was induced by BCR/ABL.
The study concluded that the deletion of FABD reduced the carcinogenic potential of BCR/ABL in vitro and in vivo, offering new insights into the role of the FABD domain in BCR/ABL function.
The study was funded by the Natural Science Foundation of Chongqing, China (No. cstc2019jcyj-msxmX0422).
Source: https://pubmed.ncbi.nlm.nih.gov/38849885/
Zheng R, Wei W, Liu S, et al. (2024). “The FABD domain is critical for the oncogenicity of BCR/ABL in chronic myeloid leukaemia.” Cell Commun Signal. 2024 Jun 7;22(1):314. doi: 10.1186/s12964-024-01694-8. PMID: 38849885; PMCID: PMC11157785.
