Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes.

Wei Li,Peng Li,Tianzhong Li,Jianyu Weng,Bing Xu,Lijian Yang,Yi Zheng,Minjie Zhang,Shaohua Chen,Donghai Wu,Jue Jiang,Xinru Wei,Zhiwu Jiang,Yangqiu Li,Hudan Liu,Hexiu Su,Pentao Liu,Suxia Geng,Yao Yao,Ming Zhong ,Xiao‐Jun Huang ,Yufeng Hu,Xin Du

doi:10.1186/s12943-014-0285-x

Abstract

BackgroundKruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. However, the roles of KLF4 in hematological malignancies and the mechanisms of action are not fully understood.MethodsInducible KLF4-overexpression Jurkat cell line combined with mouse models bearing cell-derived xenografts and primary T-cell acute lymphoblastic leukemia (T-ALL) cells from four patients were used to assess the functional role of KLF4 in T-ALL cells in vitro and in vivo. A genome-wide RNA-seq analysis was conducted to identify genes regulated by KLF4 in T-ALL cells. Chromatin immunoprecipitation (ChIP) PCR was used to determine direct binding sites of KLF4 in T-ALL cells.ResultsHere we reveal 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. We 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.ConclusionsThese results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0285-x) contains supplementary material, which is available to authorized users.

Highlights

Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner
Enforced KLF4 expression induces apoptosis in Jurkat cells through the BCL2/BCLXL pathway To investigate the function of KLF4 in Jurkat cells, the TRE-KLF4 and TRE-empty Jurkat cell lines that were constitutively GFP+ were established (Additional files 1 and 2: Figures S1-S2)
We found that Z-VAD-FMK treatments reduced the apoptotic rate of Jurkat cells with KLF4 overexpression (Figure 1d)

Summary

Introduction

Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. Klf together with Oct, Sox, and c-Myc are widely referred to as ‘Yamanaka factors’ enforced expression of which makes adult cells reprogram into pluripotent stem cells [3]. The expression levels of Klf, Sox, and Oct may need to be decreased during the differentiation of pluripotent cells [4]. Mice homozygous for a null mutation in Klf die within a day after birth and show defects in epidermis and colonic epithelial cell differentiation [5]. A recent study reports that the downregulation of Klf is required for T cell lineage commitment in mice and Klf overexpression blocks T cell development primarily at early stage through suppressing the transcription of several genes that are crucial for early T cell development [6]

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