GIBH Scientists Discovered that KLF4 can act as an important negative regulator in T-cell acute lymphoblastic leukemia

The research group led by Prof Peng Li at GIBH has recently identified that KLF4 can inhibit T-ALL progression by suppressing the expression of T-cell associated genes. KLF4, also known as GKLF (gut KLF), is a member of the KLF zinc finger-containing transcription factor family. Klf4 together with Oct4, Sox2, and c-Myc are widely referred to as ‘Yamanaka factors’ enforced expression of which makes adult cells reprogram into pluripotent stem cells. Consistently, the expression levels of Klf4, Sox2, and Oct4 may need to be decreased during the differentiation of pluripotent cells. Klf4 has critical function in development. Mice homozygous for a null mutation in Klf4 die within a day after birth and show defects in epidermis and colonic epithelial cell differentiation. A recent study reports that the downregulation of Klf4 is required for T cell lineage commitment in mice and Klf4 overexpression blocks T cell development primarily at early stage through suppressing the transcription of several genes that are crucial for early T cell development.

T-ALL is thought to result from malignant thymocytes that arise at defined stages of T cell differentiation. Moreover, the expression of certain oncogenes or mutated T cell-specific genes has been closely linked to developmental arrest at particular stages of normal T cell development.

To systematically analyze the genes regulated by KLF4 in T-ALL, Prof Li and his team revealed that KLF4 induced apoptosis through the BCL2/BCLXL pathway in human T-ALL cell lines and primary T-ALL specimens. In consistence, mice engrafted with KLF4-overexpressing T-ALL cells exhibited prolonged survival. Interestingly, the KLF4-induced apoptosis in T-ALL cells was compromised in xenografts but the invasion capacity of KLF4-expressing T-ALL cells to hosts was dramatically dampened. Moreover, they found that KLF4 overexpression inhibited T cell-associated genes including NOTCH1, BCL11B, GATA3, and TCF7. Further mechanistic studies revealed that KLF4 directly bound to the promoters of NOTCH1, BCL2, and CXCR4 and suppressed their expression. Additionally, KLF4 induced SUMOylation and degradation of BCL11B.

These results suggest that KLF4 can act as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression. This work has been published on line by Molecular Cancer (2015, DOI 10.1186/s12943-014-0285-x).

KLF4 induces apoptosis in T-ALL cells by directly suppressing BCL2 and NOTCH1 transcription as well as inducing BCL11B degradation. Picture from: http://www.molecular-cancer.com/content/14/1/26