Growth arrest-specific protein 2 (GAS2) interacts with CXCR4 to promote T-cell leukemogenesis partially via c-MYC

Although growth arrest-specific protein 2 (GAS2) promotes the growth of T-cell acute lymphoblastic leukemia (T-ALL) cells in culture, the effect of GAS2 on T-cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencing impaired T-cell leukemogenesis and decreased leukemic cell infiltration. Mechanistically, GAS2 regulated the protein expression of C-X-C chemokine receptor type 4 (CXCR4) rather than its transcript expression. Immunoprecipitation revealed that GAS2 interacted with CXCR4, and confocal analysis showed that GAS2 was partially co-expressed with CXCR4, which provided a strong molecular basis for GAS2 to regulate CXCR4 expression. Importantly, CXCR4 overexpression alleviated the inhibitory effect of GAS2 silencing on the growth and migration of T-ALL cells. Moreover, GAS2 or CXCR4 silencing inhibited the expression of NOTCH1 and c-MYC. Forced expression of c-MYC rescued the growth suppression induced by GAS2 or CXCR4 silencing. Meanwhile, GAS2 deficiency, specifically in blood cells, had a mild effect on normal hematopoiesis, including T-cell development, and GAS2 silencing did not affect the growth of normal human CD3(+) or CD34(+) cells. Overall, our data indicate that GAS2 promotes T-cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c-MYC, whereas impaired GAS2 expression has a mild effect on normal hematopoiesis. Therefore, our study suggests that targeting the GAS2/CXCR4 axis is a potential therapeutic strategy for T-ALL.

Automated summary

This study reveals that GAS2 promotes T-cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c-MYC pathway. Loss of GAS2 has a mild effect on normal hematopoiesis.