Targeting the N-cadherin/β-catenin axis with MSAB reverses malignant phenotypes in blast crisis of CML

Yingying Zhou¹Songqin Jian²Lijun Lu¹Xiaofang Li²Ruyi Qiu^2*

• ¹Taizhou First People's Hospital, Taizhou, China
• ²Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China

The molecular mechanisms underlying chronic myeloid leukemia (CML) progression from chronic phase to blast crisis remain incompletely understood. This study aimed to identify progression-specific genes and elucidate the role of N-cadherin (CDH2) in the transformation to blast crisis (BC). We analyzed the GSE4170 dataset to screen differentially expressed genes across CML phases. Functional annotations were performed via GSEA, GO, and KEGG. In vitro and in vivo models (KU812 cell line, nude mouse xenografts) were used to validate N-cadherin function. The β-catenin inhibitor MSAB was employed for mechanistic studies. Our transcriptomic analysis identified 1,294 DEGs during CML progression, with 41 "progression-specific" genes showing consistent expression trends. Among these, N-cadherin was significantly upregulated in BC patient samples. Overexpression of N-cadherin in KU812 cells pro-moted cell cycle entry and accelerated tumor growth, while concurrently suppressing the expression of granulocyte surface differentiation antigens. MSAB was found to effectively reverse these malignant features. Furthermore, a notable upregulation of CDH2 mRNA was ob-served in acute phase samples compared to those from chronic phase, indicating a potential role for CDH2 in driving the progression of CML. In conclusion, our findings elucidated the role of CDH2 in the advancement of CML through activation of Wnt/β-catenin signaling. Targeting this axis may represent a novel therapeutic strategy for BC-CML.