BCR/ABL1ΔE7‐8‐9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Issue 5 (17th June 2022)

• Record Type: Journal Article
• Authors: Tan, Yanhong; Zhang, Lingli; Zhu, Guiyang; Yang, Yuchao; Guo, Wenzheng; Chen, Lanhui; Chang, Jianmei; Xu, Yang; Muyey, Daniel Muteb; Wang, Hongwei
• Is Part Of: Hematological oncology. Volume 40:Issue 5(2022)
• Page Start: 1067
• Page End: 1075
• Publication Date: 2022-06-17
• Subjects: BCR/ABL1 -- chronic myeloid leukemia -- drug resistance -- isoform -- tyrosine kinase inhibitors; Hematological oncology -- Periodicals; Hematology; Medical Oncology; 616.99418005
• DOI: 10.1002/hon.3040
• Languages: English
• ISSNs: 0278-0232

Abstract

Abstract: In chronic myeloid leukemia (CML) patients, the involvement of the BCR/ABL1 isoform in tyrosine kinase inhibitors (TKIs) resistance has attracted lots of attention. In this work, a novel isoform that encoded truncated protein due to the deletion of ABL1 exon7, 8, and 9 was reported and named BCR/ABL1ΔE7‐8‐9 here. This isoform was detected only in 10.2% of CML patients with inadequate responses to TKIs. BCR/ABL1Δexon7‐8‐9 isoform promoted S phase cell proliferation and reduced the expression of fusion gene and ABL1 phosphorylation level more slowly than that of control cells after TKIs treatment. The novel isoform has the qualities of a functional tyrosine kinase, localized in the cytoplasm, and could not be imported into the nucleus by TKIs. These results indicated that BCR/ABL1Δexon7‐8‐9 showed poorer sensitivity to imatinib and nilotinib than wild‐type BCR/ABL1. According to molecular docking studies, nilotinib and imatinib present different binding sites and have a lower binding capacity with BCR/ABL1ΔE7‐8‐9 protein than the wild type. Our findings suggested that the novel isoform BCR/ABL1ΔE7‐8‐9 may contribute to TKIs resistance in CML due to its weakened TKIs binding ability. It enriched the mechanism of spliceosome involved in TKIs resistance. Monitoring the expression of BCR/ABL1ΔE7‐8‐9 helps guide the treatment of CML patients in the clinic.