Suppression of super-enhancer-driven TAL1expression by KLF4 in T-cell acute lymphoblastic leukemia

TAL1is one of the most frequently dysregulated genes in T-ALL and is overexpressed in about 50% of T-ALL cases. One of the molecular mechanisms of TAL1overexpression is abnormal mutations in the upstream region of the TAL1promoter that introduce binding motifs for the MYB transcription factor. MYB binding at this location creates a 5’ TAL1super-enhancer (SE), which leads to aberrant expression of TAL1and is associated with unfavorable clinical outcomes. Although targeting TAL1 is considered to be an attractive therapeutic strategy for patients with T-ALL, direct inhibition of transcription factors is challenging. Here, we show that KLF4, a known tumor suppressor in leukemic cells, suppresses SE-driven TAL1expression in T-ALL cells. Mechanistically, KLF4 downregulates MYBexpression by directly binding to its promoter and inhibits the formation of 5’ TAL1SE. In addition, we found that APTO-253, a small molecule inducer of KLF4, exerts an anti-leukemic effect by targeting SE-driven TAL1expression in T-ALL cells. Taken together, our results suggest that the induction of KLF4 is a promising strategy to control TAL1expression and could be a novel treatment for T-ALL patients with a poor prognosis.