Abstract
Biomarkers on malignant cells may confer prognostic significance. Krüppel-like factor 4 (KLF4) has been reported to be expressed variably on leukemia cells, but its expression patterns in leukemias with different differentiation stages and its relationships with clinical parameters remain to be elucidated. To examine the KLF4 expression pattern in human leukemias and its clinical significance, RT-PCR and real-time PCR were used to detect KLF4 expression in 9 leukemia cell lines and 96 pediatric leukemia patients. KLF4 mRNA expressed in 5/16 (31.25 %) of AML patients and 11/28 (39.29 %) ALL patients, significantly lower than that in control (9/11, 81.82 %, P < 0.05). The expressions of KLF4 mRNA were much lower in ALL (27/52) compared to AML (25/52) (P = 0.019), AML-M1 to other subtypes of AML (P = 0.001), C-ALL to Pre-B ALL (P = 0.004), Pro-T ALL to T-ALL (P = 0.048). Observation on leukemia cell lines showed the similar pattern. The relative expression of KLF4 mRNA was inversely associated with CD34-positive rates (r = −0.296, P = 0.037), but it was not associated with the blasts percentages in bone marrow (r = −0.222, P = 0.137) and the WBC counts (r = −0.058, P = 0.679). KLF4 mRNA expression level was not related to the overall survival (r = −0.063, P = 0.670), and the median survival times for the KLF4 Lower and KLF4 Higher groups were comparable (28 vs. 25 months, P = 0.265). Furthermore, no difference was found in KLF4 mRNA expression levels whether in leukemias with normal and abnormal karyotypes (P = 0.180), or in leukemias with normal and abnormal molecular cytogenetics (P = 0.591). We conclude that KLF4 translation level is associated with the differentiation stage of different leukemias and is independent of other parameters of risk stratification.
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References
Cullingford TE, Butler MJ, Marshall AK et al (2008) Differential regulation of Kruppel-like factor family transcription factor expression in neonatal rat cardiac myocytes: effects of endothelin-1, oxidative stress and cytokines. Biochim Biophys Acta 1783:1229–1236
Fruman DA, Ferl GZ, An SS et al (2002) Phosphoinositide 3-kinase and Bruton’s tyrosine kinase regulate overlapping sets of genes in B lymphocytes. Proc Natl Acad Sci USA 99:359–364
Evans PM, Liu C (2008) Role of Krüppel-like factor 4 in normal homeostasis, cancer and stem cells. Acta Biochim Biophys Sin (Shanghai) 40:554–564
Schuetz A, Nana D, Rose C et al (2011) The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell Mol Life Sci 68:3121–3131
Katz JP, Perreault N, Goldstein BG et al (2012) The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 129:2619–2628
Zhao W, Hisamuddin IM, Nandan MO et al (2004) Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 23:395–402
Wei D, Gong W, Kanai M et al (2005) Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 65:2746–2754
Ohnishi S, Ohnami S, Laub F et al (2003) Downregulation and growth inhibitory effect of epithelial-type Kruppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem Biophys Res Commun 308:251–256
Pandya AY, Talley LI, Frost AR et al (2004) Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res 10:2709–2719
Chen YJ, Wu CY, Chang CC et al (2008) Nuclear Krüppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis. Cancer Biol Ther 7:777–782
Kharas MG, Yusuf I, Scarfone VM et al (2007) KLF4 suppresses transformation of pre-B cells by ABL oncogenes. Blood 109:747–755
Yasunaga J, Taniguchi Y, Nosaka K et al (2004) Identification of aberrantly methylated genes in association with adult T-cell leukemia. Cancer Res 64:6002–6009
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Res 29:45
Witte KE, Ahlers J, Schäfer I et al (2011) High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia. Pediatr Hematol Oncol 28:91–99
Ebinger M, Witte KE, Ahlers J et al (2010) High frequency of immature cells at diagnosis predicts high minimal residual disease level in childhood acute lymphoblastic leukemia. Leuk Res 34:1139–1142
Van Rhenen A, Feller N, Kelder A et al (2005) High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 11:6520–6527
Zhu X, Hart R, Chang MS et al (2004) Analysis of the major patterns of B cell gene expression changes in response to short-term stimulation with 33 single ligands. J Immunol 173:7141–7149
Van Zelm MC, van der Burg M, de Ridder D et al (2005) Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. J Immunol 175:5912–5922
Feinberg MW, Wara AK, Cao Z et al (2007) The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J 26:4138–4148
Kong Y, Yoshida S, Saito Y et al (2008) CD34+CD38+CD19+ as well as CD34+CD38−CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia 22:1207–1213
Kahng Jimin, Shin So-Young, Han Kyungja (2007) Proportions of cells expressing CD38−/CD34+, CD38+/CD34+, CD19+/CD34+, or CD13,33+/CD34+ in the regenerating bone marrows during complete remission of acute leukemia or after bone marrow transplantation. Korean J Lab Med 27:406–413
Van Grotel M, Van den Heuvel-Eibrink MM, Van Wering ER et al (2008) CD34 expression is associated with poor survival in pediatric T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 51:737–740
Babusikova O, Stevulova L, Fajtova M (2009) Immunophenotyping parameters as prognostic factors in T-acute leukemia patients. Neoplasma 56:508–513
Marisavljevic D, Kraguljac-Kurtovic N (2010) Biological implications of circulating CD34 (+) cells in myelodysplastic syndromes. J Buon 15:753–757
Den Heuvel-Eibrink MMV, Der Holt BV, Burnett AK et al (2007) CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age. Ann Hematol 86:329–337
Yong AS, Rezvani K, Savani BN et al (2007) High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects. Blood 110:770–775
Acknowledgments
This study was supported in part by Grants from the National Natural Scientific Fund of China (No: 30170391, No: 30971283, No: 81170502), the Zhejiang Provincial Fund of Natural Science (No: Z205166), and the Zhejiang Provincial Fund of Science and Technology Bureau (No: 2007C23007). We also would like to thank Mr. Hongqiang Shen and Mrs Baiqin Qian for their excellent technical support.
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Guo, X., Tang, Y. KLF4 translation level is associated with differentiation stage of different pediatric leukemias in both cell lines and primary samples. Clin Exp Med 13, 99–107 (2013). https://doi.org/10.1007/s10238-012-0187-4
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DOI: https://doi.org/10.1007/s10238-012-0187-4