Alternative splicing of Ikaros regulates the FUT4/Le-α5β1 integrin-FAK axis in acute lymphoblastic leukemia.

Unveiling the mechanism of the relapse of acute lymphoblastic leukemia (ALL) is the key to improve the prognosis of ALL and remains a huge challenge. Glycan-based interactions play a vital role in immune surveillance, cell-cell adhesion and cell-matrix interaction, contributing to treatment failure in tumor. However, the glycan essential for leukemia development and its upstream regulatory mechanism by oncogenic drivers were rarely reported. Here, we demonstrated that Le, a well-characterized cancer-related glycan epitope, strengthened the cell-matrix interaction via glycosylating α5β1 integrin under the control of the driver oncogenic Ikaros isoform (IK6) in ALL. By analyzing the expression profile of Ikaros and the level of FUT4/Le in clinical samples, we found that FUT4/Le was positively correlated with dysfunctional Ikaros isoforms. IK1 (Full length Ikaros) regulates the level of FUT4 as a transcription repressor, while IK6 abolished the wild-type Ikaros mediated transcriptional repression and resulted in higher level of FUT4 expression. Moreover, we demonstrated that FUT4 could activate α5β1-mediated sequential signal transduction and accelerate adhesion and invasion between integrin α5β1 in leukemia cells and fibronectin in extracellular matrix (ECM) via increasing glycosylation. Together, our study provides a new insight into the mechanisms by which Ikaros mutation induced ALL cells invasion and a potential strategy for drug-resistance ALL by blocking Le in combination with common chemotherapy.