ALK^ATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma

Soft tissue sarcoma (STS) is a highly malignant tumor with limited targeted therapies. A novel anaplastic lymphoma kinase (ALK) transcript, ALK^ATI, was identified recently and could be targeted by ALK inhibitors in melanoma. However, the clinical and functional role of aberrant ALK^ATI expression in STS remains unknown. Here we demonstrate that as a new ALK transcript, ALK^ATI is frequently found in STS. ALK^ATI expression correlates with a lower probability of progression-free survival in STS patients. Compared with the other ALK isoforms, ALK^ATI expresses not only in the cytoplasm, but also in the nucleus of sarcoma cells. Functionally, overexpression of ALK^ATI promoted cancer stem cell (CSC)-like properties in sarcoma cells by promoting sphere formation and upregulating the expression of stem cell markers. Moreover, the ALK inhibitors not only suppressed the oncogenic functions of ALK^ATI but also attenuated ALK^ATI-induced CSC-like properties by reducing the expression of stem cell markers such as c-Myc, ABCG2, BMI1, and OCT4 both in vitro and in vivo. Furthermore, ALK^ATI interacted with c-Myc and increased the binding of c-Myc to the ABCG2 promoter, resulting in the induction of stem cell-like properties. Together, these findings indicate that ALK^ATI may be a potential prognostic marker and therapeutic target for STS patients harboring such ALK aberrations.