Induction of T-Cell Differentiation by KLF4 in T-Cell Acute Lymphoblastic Leukemia Cells Harboring Activating Mutation in NOTCH3

Krüppel-like factor 4 (KLF4) exhibits both oncogenic and tumor-suppressive effects depending on the type of cancer and cellular context. In T-cell acute lymphoblastic leukemia (T-ALL), KLF4 expression is silenced by promoter methylation, and the induction of KLF4 suppresses the proliferation of T-ALL cells. Therefore, KLF4 is thought to function as a tumor suppressor in T-ALL cells; however, its role in the differentiation of T-ALL cells remains unclear. Here, we show that KLF4 induced T-cell differentiation and apoptosis in TALL-1 cells harboring an activating mutation in NOTCH3. Mechanistically, KLF4 directly downregulated NOTCH3 expression by binding to its promoter, thereby promoting the differentiation of CD4/CD8 double-positive cells into CD4 single-positive cells, with the differentiated cells subsequently undergoing apoptosis. Furthermore, we found that APTO-253, a small-molecule inducer of KLF4, effectively suppressed cell growth in TALL-1 cells by promoting T-cell differentiation followed by apoptotic cell death. These findings suggest a promising strategy for developing novel differentiation therapies for T-ALL with NOTCH3 mutations.