Noura Mina, Yasuda Takahiko, Kiyoi Hitoshi, Hayakawa Fumihiko
Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
FASEB J. 2025 May 31;39(10):e70613. doi: 10.1096/fj.202402997R.
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.
Krüppel样因子4（KLF4）根据癌症类型和细胞环境表现出致癌和肿瘤抑制作用。在T细胞急性淋巴细胞白血病（T-ALL）中，KLF4的表达因启动子甲基化而沉默，KLF4的诱导抑制了T-ALL细胞的增殖。因此，KLF4被认为在T-ALL细胞中起肿瘤抑制作用；然而，其在T-ALL细胞分化中的作用仍不清楚。在此，我们表明KLF4在携带NOTCH3激活突变的TALL-1细胞中诱导T细胞分化和凋亡。机制上，KLF4通过结合NOTCH3启动子直接下调其表达，从而促进CD4/CD8双阳性细胞分化为CD4单阳性细胞，随后分化细胞发生凋亡。此外，我们发现KLF4的小分子诱导剂APTO-253通过促进T细胞分化并随后导致凋亡性细胞死亡，有效抑制了TALL-1细胞的生长。这些发现为开发针对具有NOTCH3突变的T-ALL的新型分化疗法提供了一个有前景的策略。
