KLF4/MLL3 Compass Complex Regulates NRBP2 to Eliminate Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) is recognized as a complex disease involving hematopoietic stem cell disorders. Despite advanced in therapy, the prognosis for AML patients remains poor. Previous studies by our group and others have demonstrated that krüppel-like factor 4 (KLF4), a transcription factor, inhibited AML through microRNA networks or p57 signaling pathway. In our previous studies, we found that overexpression of the YAMANAK factor (OSKM) in AML cells induced apoptosis, with KLF4 playing a significant role. However, the mechanisms through which KLF4 regulates gene transcription and histone modifications in AML remain elusive and require further investigation. In this study, we demonstrated that the overexpression of KLF4 inhibited AML proliferation, induced cell apoptosis, and prolonged the survival of AML mice. Co-inmmunoprecipitation (Co-IP) and mass spectrometry analysis verified that KLF4 interacted with the MLL3 CAMPASS complex, including MLL3/4, WDR5, RBBP5 and others. To investigate the mechanisms, we generated different truncated forms of KLF4 and showed that the zinc finger (ZnF) and TRD domains of KLF4 were crucial for the elimination of AML cells, as evidenced by cell viability experiments. In addition, we conducted RNA-seq, ATAC-seq and ChIP-seq in KLF4 overexpressing THP-1 cells. The results indicated that KLF4 regulated the transcription of NRBP2. Interestingly, downregulation of MLL3 led to a decrease in the luciferase activity of NRBP2. Furthermore, the increased cell apoptosis and impaired cell proliferation induced by overexpression of KLF4 could be rescued by knocking down NRBP2. Consequently, KLF4 promoted AML pathogenesis by interacting with the MLL3 CAMPASS complex and facilitating the transcription of NRBP2. These findings indicate that the KLF4-MLL3 CAMPASS-NRBP2 axis plays a crucial role in AML cells and suggests a potential therapeutic target for the disease.

No relevant conflicts of interest to declare.