Expression profile of WNT, FZD and sFRP genes in human hematopoietic cells

Sercan, Zeynep; Pehlivan, Melek; Sercan, Hakki Ogun

doi:10.1016/j.leukres.2010.02.009

Cited by 16 publications

(16 citation statements)

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“…A clear effect on the inhibition of proliferation was observed in all cases. In contrast to our observations, FZD6 expression has been reported to be present in K562 and HL60 by other authors [21,39]; however, in both reports, FZD6 expression was analyzed only at the mRNA level (Northern blot and PCR). This suggests that other receptors/co-receptors must be involved in WNT4 signaling and that the molecules involved are dependent on the cell type.…”

Section: Discussioncontrasting

confidence: 99%

“…Variations in WNT gene expression and the related signaling molecules have been reported in hematological cancers [21-23]. However, the function of WNT4 in leukemia, to our knowledge, has not yet been described; therefore, the goal of our research was to determine the expression of the WNT4 ligand in leukemia-derived cells, the effect of its expression on cell growth and apoptosis, and the WNT signaling pathway activated in our cell model.…”

Section: Introductionmentioning

confidence: 99%

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Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

et al. 2013

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BackgroundWNT signaling pathways are significantly altered during cancer development. Vertebrates possess two classes of WNT signaling pathways: the “canonical” WNT/β-catenin signaling pathway, and the “non-canonical” pathways including WNT/Ca2+ and WNT/Planar cell polarity [PCP] signaling. WNT4 influences hematopoietic progenitor cell expansion and survival; however, WNT4 function in cancer development and the resulting implications for oncogenesis are poorly understood.The aim of this study was twofold: first, to determine the expression of WNT4 in mature peripheral blood cells and diverse leukemia-derived cells including cell lines from hematopoietic neoplasms and cells from patients with leukemia; second, to identify the effect of this ligand on the proliferation and apoptosis of the blast-derived cell lines BJAB, Jurkat, CEM, K562, and HL60.MethodsWe determined WNT4 expression by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) and T- and B-lymphocytes from healthy individuals, as well as from five leukemia-derived cell lines and blasts derived from patients with leukemia. To analyze the effect of WNT4 on cell proliferation, PBMCs and cell lines were exposed to a commercially available WNT4 recombinant human protein. Furthermore, WNT4 expression was restored in BJAB cells using an inducible lentiviral expression system. Cell viability and proliferation were measured by the addition of WST-1 to cell cultures and counting cells; in addition, the progression of the cell cycle and the amount of apoptosis were analyzed in the absence or presence of WNT4. Finally, the expression of WNT-pathway target genes was measured by qRT-PCR.ResultsWNT4 expression was severely reduced in leukemia-derived cell lines and blasts derived from patients with leukemia. The exposure of cell lines to WNT4 recombinant protein significantly inhibited cell proliferation; inducing WNT4 expression in BJAB cells corroborated this observation. Interestingly, restoration of WNT4 expression in BJAB cells increased the accumulation of cells in G1 phase, and did not induce activation of canonical WNT/β-catenin target genes.ConclusionsOur findings suggest that the WNT4 ligand plays a role in regulating the cell growth of leukemia-derived cells by arresting cells in the G1 cell cycle phase in an FZD6-independent manner, possibly through antagonizing the canonical WNT/β-catenin signaling pathway.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

et al. 2013

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“…In agreement with this observation, Lu et al also found expression of this ligand in peripheral blood lymphocytes (ΔCP 11.81 ± 0.99), but do not determined that this expression was afforded mainly from T-cells [19]. In contrast, Sercan et al found WNT7A expression in both T- and B-cells obtained from healthy volunteers [23]. Discrepancies in these data could be due to the different method employed for quantification.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, different expression profiles of some WNT genes and their related signaling molecules have been reported in hematological cancers [12,18-22]. However, there are limited numbers of studies regarding the role of WNT7a, both in normal and in leukemia-derived cells [19,23,24]. …”

Section: Introductionmentioning

confidence: 99%

Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation

Ochoa-Hernández

Ramos-Solano²,

Meza-Canales³

et al. 2012

BMC Cancer

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BackgroundWNT7a, a member of the Wnt ligand family implicated in several developmental processes, has also been reported to be dysregulated in some types of tumors; however, its function and implication in oncogenesis is poorly understood. Moreover, the expression of this gene and the role that it plays in the biology of blood cells remains unclear. In addition to determining the expression of the WNT7A gene in blood cells, in leukemia-derived cell lines, and in samples of patients with leukemia, the aim of this study was to seek the effect of this gene in proliferation.MethodsWe analyzed peripheral blood mononuclear cells, sorted CD3 and CD19 cells, four leukemia-derived cell lines, and blood samples from 14 patients with Acute lymphoblastic leukemia (ALL), and 19 clinically healthy subjects. Reverse transcription followed by quantitative Real-time Polymerase chain reaction (qRT-PCR) analysis were performed to determine relative WNT7A expression. Restoration of WNT7a was done employing a lentiviral system and by using a recombinant human protein. Cell proliferation was measured by addition of WST-1 to cell cultures.ResultsWNT7a is mainly produced by CD3 T-lymphocytes, its expression decreases upon activation, and it is severely reduced in leukemia-derived cell lines, as well as in the blood samples of patients with ALL when compared with healthy controls (p ≤0.001). By restoring WNT7A expression in leukemia-derived cells, we were able to demonstrate that WNT7a inhibits cell growth. A similar effect was observed when a recombinant human WNT7a protein was used. Interestingly, restoration of WNT7A expression in Jurkat cells did not activate the canonical Wnt/β-catenin pathway.ConclusionsTo our knowledge, this is the first report evidencing quantitatively decreased WNT7A levels in leukemia-derived cells and that WNT7A restoration in T-lymphocytes inhibits cell proliferation. In addition, our results also support the possible function of WNT7A as a tumor suppressor gene as well as a therapeutic tool.

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“…It was suggested that these genes might have different roles as indicated by differential expression patterns in hematopoietic cells. 40 In particular, SFRP1 expression was recently found to be down-regulated in patients with AML, myelodysplastic syndrome, and acute lymphoblastic leukemia. 41 In this study, we found that SFRP1 but not other SFRP genes was a transcriptional repression target of the RUNX1-ETO fusion protein in AML.…”

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confidence: 99%

Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia

Cheng¹,

Li²,

Cheng³

et al. 2011

Blood

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Secreted-frizzled related proteins (SFRPs) are modulators of the Wnt signaling pathway that is closely involved in normal and malignant hematopoiesis. Epigenetic deregulation of Wnt modulators leading to aberrant signaling has been reported in adult patients with acute myeloid leukemia (AML), but its occurrence in childhood patients with AML and the role of individual modulators are unclear. In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)-leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with concomitant down-regulation of Wnt/␤-catenin target genes, including CCND1 and MYC. Taken IntroductionThe Wnt signaling pathway is an important regulator of hematopoietic cell fate and growth. 1,2 Deregulation of this pathway has been implicated in human leukemogenesis. 3 Wnt signaling comprises the canonical pathway with ␤-catenin as a central mediator and noncanonical pathways primarily involving Ca 2ϩ ions and planar cell polarity. 4 Signal transduction by Wnts is tightly regulated by several families of extracellular modulators, among which secreted frizzled-related proteins (SFRPs) are the largest family. 4 SFRPs are generally regarded as Wnt antagonists. However, they can also activate Wnt signaling and interfere with other signaling pathways through Wnt-independent mechanisms. 4 In humans, 5 SFRP genes (SFRP1, SFRP2, SFRP3, SFRP4, and SFRP5) have been identified, and 4 of these genes except SFRP3 contain dense CpG islands around their promoter regions. Interestingly, previous studies reported that SFRP1, SFRP2, SFRP4, SFRP5, and other Wnt modulators were silenced by promoter hypermethylation in different cancers, including acute myeloid leukemia (AML), and this epigenetic silencing was associated with aberrant Wnt activation. [5][6][7][8] Moreover, in AML, the Wnt signaling can also be activated by mutant fms-like tyrosine kinase 3 (FLT3) and common translocationassociated fusion proteins. 9,10 Collectively, these findings indicate that Wnt signaling aberration involves multiple mechanisms and is a common molecular feature in different biologic subtypes of AML.t(8;21)(q22;q22) is the most frequent karyotypic abnormality in AML, representing ϳ 15% of total cases, and is associated with the French-American-British (FAB) M2 subtype. 11 t(8;21) fuses the N-terminal portion of RUNX1, including its Runt domain, to most of the eight-twenty-one (E...

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Expression profile of WNT, FZD and sFRP genes in human hematopoietic cells

Cited by 16 publications

References 9 publications

Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation

Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia

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