KLF4 suppresses transformation of pre-B cells by ABL oncogenes

Abstract

IntroductionThe Krüppel-like factor (KLF) family of transcription factors is related to the protein Krüppel in Drosophila melanogaster. 1,2 KLFs regulate cell-fate decisions, including development and differentiation of specific tissues. Each contains 3 conserved zinc finger DNA-binding motifs in the c-terminal domain and bind GC-rich regions with a consensus sequence of "CACCC." The functional specificity of distinct KLF family members is maintained through the transactivation and/or repression domains in the N-terminus of the protein and through differential tissue expression. KLF4 is highly expressed in epithelial tissues, and mouse genetic models have established a role for Klf4 in terminal epidermal differentiation. 3,4 KLF4 is also highly expressed in resting lymphocytes but strongly down-regulated in activated cells. 5,6 During human B-cell development, KLF4 is differentially expressed, with greater levels of mRNA in the small pre B-I and pre B-II stages compared with the large pre-B-cell stage. 7 Thus, KLF4 expression in the B lineage correlates with stages with low proliferation, implying a role in B-cell development similar to its function in terminal skin differentiation.Many KLFs have been implicated in suppression of proliferation. For example, KLF6 is a tumor suppressor in human prostate cancer, and disruption of KLF3 (BKLF) function induces a myeloproliferative disorder in mice. 8,9 KLF2, the isoform most closely related to KLF4, has been established as a quiescence factor in T lymphocytes. 10,11 KLF4 itself has been identified as a tumor suppressor gene in colon and gastric cancer based on studies that show loss of heterozygosity, and is also down-regulated in bladder cancer. 12-14 KLF4 promotes cellcycle arrest as shown by serum withdrawal and overexpression studies in multiple cell lines including in NIH 3T3 fibroblasts and RKO cells (a colonic epithelial cancer cell line). 15 KLF4 is up-regulated upon DNA damage in a p53-dependent fashion and can prevent both G 1 -to-S transition and G 2 -to-M transitions in colon cancer cell lines. 15-17 KLF4 promotes expression of the cell-cycle inhibitor protein p21 CIP but in situations where p21 CIP is inactivated, KLF4 can act as a tumor promoter by suppressing p53. 18,19 In a fraction of patients with B-cell acute lymphoblastic leukemia (B-ALL), tumor cells carry the Philadelphia (Ph) chromosome (9;22). The translocation encodes a fusion protein combining the breakpoint cluster region (BCR) protein with the Abelson tyrosine kinase (ABL). 20 Although the ABL kinase inhibitor imatinib has been effective with patients with Ph ϩ chronic myelogenous leukemia, appearance of resistance to this compound has mitigated the prospect of a cure for this leukemia. Furthermore, acute lymphoblastic leukemia caused by BCR-ABL is more refractory to treatment. 21 BCR-ABL, and the related murine oncoprotein v-Abl, activate many mitogenic signaling enzymes and transcription factors that have been extensively studied. 22,23 Identifying factors that must be silenced or inacti...

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

“…Application of COPA to the expression profiles of the 136 human AML cases demonstrated that of the putative CDX2 effectors shown in Figure 1C, only KLF4 and G0S2 were among the top-ranking outliers at the 95th percentile, showing markedly decreased expression in patients with high CDX2 mRNA levels ( Figure 1D). These observations, together with previous data showing that KLF4 functions as a tumor suppressor in certain gastrointestinal cancers (32)(33)(34) and B cell malignancies (35,36), suggested that suppression of KLF4 might be one mechanism whereby CDX2 promotes leukemogenesis.…”

KLF4 Modulates Expression of IL-6 in Dendritic Cells via Both Promoter Activation and Epigenetic Modification

“…: (25)(26)(27)(28)(29)(30)(31)(32). Because of its known role as a transcription factor, we sought to systematically determine how it interacted with the IL-6 promoter.…”

Kruppel-like factor 4 blocks tumor cell proliferation and promotes drug resistance in multiple myeloma

“…with a KLF4 signal ≥mean value + 2 SD in normal BMPC) and 30% of the patients had a very weak KLF4 signal <100. The KLF4 gene was not expressed by any of 18 HMCL (median value 5, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Using western blot analysis, KLF4 protein could be detected in the five samples of purified primary MMC in which the KLF4 gene was expressed (Online Supplementary Figure S1B).…”

“…3 However, KLF4 is also a so-called stem cell protein. It is one of Yamanaka's four proteins (OCT4, SOX2, KLF4 and MYC) able to reprogram adult cells into induced pluripotent stem cells.…”