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Myeloid leukemia factors (MLF1 and MLF2) are proteins associated with leukemia and several other cancers. However, little is known about the regulatory mechanisms underlying the stability of these proteins. Here, we show that DDB1 and CUL4 associated factor 8 (DCAF8), which can form a functional E3 ligase complex (CRL4DCAF8), has a strong interaction with the MLF2 protein. DCAF8 could promote MLF2 degradation through the ubiquitin-proteasome pathway. In contrast, ubiquitin specific peptidase 11 (USP11) associates with MLF2, thereby increasing its stability. Since MLF1 is highly related to MLF2, we demonstrated that MLF1 also interacts with DCAF8 and USP11, suggesting that CRL4DCAF8 and USP11 may also regulate the expression of MLF1. TCGA analysis revealed that both the myeloid leukemia factors (MLF1 and MLF2) show significant differential expression in various tumors. The results of our study indicate that CRL4DCAF8 and USP11 play opposite roles in the regulation of MLF1 and MLF2, which may, in turn, affect their biological functions in various cancers. • MLF2 associates with CRL4DCAF8 complex. • DCAF8 promotes the proteasomal degradation of MLF2. • USP11 stabilizes the levels of MLF2. • CRL4DCAF8 and USP11 may regulate protein levels of MLF1. [ABSTRACT FROM AUTHOR]