FBXO22 targets ubiquitination and degradation of c-Cbl in leukemia

Leukemia is a malignant clonal disease originating from hematopoietic stem cells. Uncontrolled proliferation, impaired differentiation and maturation, accompanied by reduced apoptosis is the most significant feature of leukemia. It has been suggested that c-Cbl is involved in the development of myeloid leukemia, but the upstream signal regulating its activity remains unclear. FBXO22 is an E3 ubiquitin ligase belonging to the F-box protein family. We constructed stable cell lines of the overexpression of FBXO22 and c-Cbl, the knockdout of c-Cbl as well as FBXO22 + c-Cbl co-transfection. We used CCK-8 and FACS to measure the cell viability, cell cycle and cell differentiation, respectively. After overexpression of FBXO22, the proliferation of U937 and K562 cells was slowed down, the pro-apoptotic proteins were increased, the anti-apoptotic proteins were decreased, and the cells differentiated into the next stage. The result of c-Cbl knockdown was consistent with that of FBXO22 overexpression. Overexpression of c-Cbl showed the opposite result. In vivo experiments also showed that both FBXO22 overexpression and c-Cbl knockdown could inhibit the occurrence and development of leukemia. Immunoprecipitation result showed that FBXO22 interacted with c-Cbl and promoted ubiquitination and degradation of c-Cbl. Moreover, the results of rescue experiments showed that c-Cbl reversed the function of FBXO22 on leukemia cells. We identified that FBXO22 interacts with c-Cbl and promotes its ubiquitination and degradation to act as a tumor suppressor gene in leukemia. Our studies suggested that FBXO22 plays an anticancer role by mediating ubiquitination and degradation of c-Cbl in leukemia.