Frequent Epigenetic Inactivation of MSX2 In Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4645-4645 ◽  
Author(s):  
Chen Zhao ◽  
Xin Han ◽  
Yu H. Zhang ◽  
Xiaoyan Huang ◽  
Aili Dai ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Functional Role ◽  
Methylation Status ◽  
Dna Hypermethylation ◽  
Expression Levels ◽  
Mrna Expression Levels ◽  
Acute Myeloid

Abstract Abstract 4645 DNA hypermethylation has been implicated in the tumorigenesis and prognosis in acute myeloid leukemia (AML). To identify and validate relevant methylated genes in AML, we have compared expression levels and methylation status of 26 candidate genes. One of the interesting candidates identified in our study is MSX2. MSX2 is a member of muscle segment homeobox gene family. MSX2 plays a role in promoting cell growth under certain conditions and may be an important target for RAS signaling pathways. However, the mechanism of transcriptional regulation and functional role of MSX2 in hematological malignancies, especially AML, are poorly understood. In our study, we determined the methylation status, and analyzed the expression levels of MSX2 in AML cell lines and primary AML cells using RT-PCR and/or Taqman real-time PCR. MSX2 mRNA expression was robust in the normal granulocytes and blasts of human bone-marrow, but was either absent or significantly diminished in 6 of 9 (66.7%) AML cell lines. The expression levels of MSX2 in those 6 AML cell lines were restored after treatment of 5-aza 2′-deoxycytidine. In addition, COBRA (Combined Bisulfite Restriction) analysis demonstrated hypermethylation of MSX2 in those AML cell lines (6 of 9, 66.7%), and partial methylation in 3 of 9 AML cell lines. The methylation status was inversely correlated with the mRNA expression levels of MSX2 in those cell lines. Furthermore, the expression levels and methylation status of MSX2 in human primary AML cells were evaluated. COBRA analysis demonstrated frequent hypermethylation of MSX2 in primary AML patient samples (19 of 32, 59.3%). Importantly, the mRNA expression levels of MSX2 as shown by Taqman real-time PCR in those 19 primary AML patient samples were inversely correlated with the methylation status of MSX2. These findings confirmed the role of frequent DNA hypermethylation in silencing MSX2 in AML. We are in the process of determining the functional role of MSX2 in the pathogenesis of AML. In addition, diagnostic and prognostic values of MSX2 in AML are being pursued. Disclosures: No relevant conflicts of interest to declare.

scholarly journals TRIM31 promotes acute myeloid leukemia progression and sensitivity to daunorubicin through the Wnt/β-catenin signaling

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Yi Xiao ◽  
Taoran Deng ◽  
Xi Ming ◽  
Jinhuang Xu
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Mrna Levels ◽  
Transfected Cells ◽  
Expression Levels ◽  
Acute Myeloid

Abstract Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.

scholarly journals Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer

2021 ◽  
Vol 28 (5) ◽  
pp. 4080-4092
Author(s):  
Takahiro Ichikawa ◽  
Masahiro Shibata ◽  
Takahiro Inaishi ◽  
Ikumi Soeda ◽  
Mitsuro Kanda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Mrna Expression ◽  
Cell Lines ◽  
Mrna Levels ◽  
Pcr Array ◽  
Array Analysis ◽  
Expression Levels ◽  
Er Positive ◽  
Mrna Expression Levels

Background: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers; however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. Methods: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients’ clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. Results: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. Conclusion: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

scholarly journals A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia

2020 ◽  
pp. mcp.RA120.002169
Author(s):  
Ka-Won Kang ◽  
Hyoseon Kim ◽  
Woojune Hur ◽  
Jik-han Jung ◽  
Su Jin Jeong ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Extracellular Vesicle ◽  
The Cancer Genome Atlas ◽  
Enzyme Linked Immunosorbent Assay ◽  
Expression Levels ◽  
Proteomic Approach ◽  
Cancer Genome Atlas ◽  
Acute Myeloid

Extracellular vesicle (EV) proteins from acute myeloid leukemia (AML) cell lines were analyzed using mass spectrometry. The analyses identified 2450 proteins, including 461 differentially expressed proteins (290 upregulated and 171 downregulated). CD53 and CD47 were upregulated and were selected as candidate biomarkers. The association between survival of patients with AML and the expression levels of CD53 and CD47 at diagnosis was analyzed using mRNA expression data from The Cancer Genome Atlas database. Patients with higher expression levels showed significantly inferior survival than those with lower expression levels. Enzyme-linked immunosorbent assay results of the expression levels of CD53 and CD47 from EVs in the bone marrow of patients with AML at diagnosis and at the time of complete remission with induction chemotherapy revealed that patients with downregulated CD53 and CD47 expression appeared to relapse less frequently. Network model analysis of EV proteins revealed several upregulated kinases, including LYN, CSNK2A1, SYK, CSK, and PTK2B. The potential cytotoxicity of several clinically applicable drugs that inhibit these kinases was tested in AML cell lines. The drugs lowered the viability of AML cells. The collective data suggest that AML-derived EVs could reflect essential leukemia biology.

scholarly journals Decreased PERP Expression on Peripheral Blood Mononuclear Cells from Patient with Rheumatoid Arthritis Negatively Correlates with Disease Activity

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yanchun Du ◽  
Lin Deng ◽  
Yan Li ◽  
Lu Gan ◽  
Yantang Wang ◽  
...  
Keyword(s):  
Disease Activity ◽  
Mrna Expression ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Expression Levels ◽  
Cell Type Specific ◽  
Mrna Expression Levels

Background. PERP, p53 apoptosis effector related to PMP-22, is a p53-dependent apoptosis in diverse cell types and has cell type-specific roles in p53-mediated apoptosis. However, its role in PBMCs of RA patients has remained largely unclear.Objectives. The aim of this study was to detect the expression levels of PERP on PBMCs of RA patients and healthy controls and analyze the role of PERP in the pathogenesis of RA.Methods. The mRNA expression levels of PERP and IL-17 were detected by real-time PCR in PBMCs from patients with RA (n=40) and healthy controls (n=40). The correlations of PERP expression levels to IL-17 transcripts and disease activity parameters were analyzed.Results. The PERP and IL-17 expression levels in the PBMCs were significantly decreased and increased in comparison of which in healthy controls. The mRNA expression levels of PERP in PBMCs from patients with RA were negatively correlated with IL-17 and disease activity parameters DAS28, RF, CRP, and ESR rather than Anti-CCP and ANA.Conclusions. These results demonstrated that PERP might be involved in the pathogenesis and a potential therapeutic target of RA by regulating the expression of IL-17.

Epigenetic Inactivation of DBC1 in Acute Myeloid Leukaemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4429-4429
Author(s):  
Chen Zhao ◽  
Aili Dai ◽  
Ling Chen ◽  
Xiaoping Sun ◽  
Xin Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Acute Myeloid

Abstract Abstract 4429 DNA hypermethylation has important implications in the tumorigenesis and prognosis in acute myeloid leukemia (AML). To identify relevant methylated genes in AML, we have compared several expression and methylation profilings. With expression analysis, we identified that TRPC6, DBC1, DCC and SOX9 have decreased expression levels in the most analyzed AML cell lines. Among these candidates, DBC1 (deleted bladder cancer 1), a putative tumor suppressor, drew our attention because it is frequently methylated not only in hematological malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and acute lymphoblastic leukemia, but also in epithelial cancers. DBC1 may play an important role in the regulation of cell growth and programmed cell death. But the mechanisms of transcriptional control and function role in the hematological malignancies, especially on acute myeloid leukemia, are not well known. In this study, we analyzed the DBC1 expression pattern in 9 AML cell lines with RT-PCR analysis. DBC1 mRNA expression was observed in normal bone-marrow but diminished expression in all of 9 AML cell lines. DBC1 methylation was frequently observed in AML cells (9 of 9, 100%) and inversely correlated with DBC1 mRNA expression in a COBRA analysis (Combined Bisulfite Restriction Analysis). We also detected a frequent methylation of DBC1 in primary AML patient samples (9 of 9, 100%). These findings indicate that DBC1 is frequently silenced by hypermethylation in AML. We are in the process of investigation the functional role of DBC1 in the pathogenesis. In addition, diagnostic and prognostic values of DBC1 in AML are being pursued.* Chen Zhao and Aili Dai contributed equally to the presented work. Disclosures: No relevant conflicts of interest to declare.

Association Between RUNX3 Hypermethylation and Acute Myeloid Leukemia Inv(16) Subtype

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3548-3548
Author(s):  
Marcos R Estecio ◽  
Sirisha Maddipoti ◽  
Courtney D. DiNardo ◽  
Hui Yang ◽  
William S Stevenson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Leukemia Cell Lines ◽  
Runx3 Gene ◽  
Acute Myeloid

Abstract The RUNX family of transcription factors forms the DNA binding α-chain partners of the heterodimeric core binding factor (CBF) complex. Each of the RUNX proteins, RUNX1, RUNX2, and RUNX3, can form heterodimers with CBFβ. In the M4Eo subtype of human acute leukemia, the chromosomal translocation resulting in inversion 16 encodes a chimeric protein in which CBFβ is fused to smooth muscle myosin heavy chain (SMMHC). Although the exact mechanism of leukemogenesis by this chimera is unknown, it is thought that CBFβ-SMMHC sequesters RUNX1 in the cytoplasm and antagonizes its normal function. Although the role of RUNX1 in hematopoiesis has been previously well-established, recent data have indicated that the RUNX3 gene may also play a key role in the development of human acute leukemias. To clarify the role of RUNX3 in acute myeloid leukemia (AML), we investigated its expression and promoter DNA methylation in leukemia cell lines and patient samples. Eleven human leukemia cell lines of myeloid origin and twelve of lymphoid origin were used in this study. Cell suspensions from bone marrow aspirate specimens from patients with AML (69 cases), MDS (19 cases) and ALL (6 cases) were obtained prior to therapy from established tissue blocks. Peripheral blood samples were obtained from four healthy volunteers, and CD34+ cells were obtained from another four individuals. Methylation status of the gene promoters of RUNX1, RUNX2 and RUNX3 were evaluated using the Pyrosequencing Methylation Assay (PMA) method, and expression of RUNX3 was analyzed by quantitative real-time PCR and immunohistochemical staining. Hypermethylation of RUNX1 and RUNX2 was rare in cell lines; RUNX1 was not hypermethylated in any of the studied samples, and RUNX2 was hypermethylated in only two cell lines. In contrast, we found that the RUNX3 promoter was hypermethylated in 17 of the cell lines (74%). Interestingly, we observed a trend toward higher frequency of hypermethylation of RUNX3 in cell lines of myeloid (90%) compared to lymphoid (57%) origin. In patient samples, RUNX3 promoter methylation was below 15% in normal samples, and hypermethylation was found in 32/69 AML samples (46%), 4/19 MDS samples (21%), and 6/6 ALL samples (100%). Of the 69 AML samples, 19 were classified as AML M4Eo, and 50 were other types of AML. 84% of the human AML M4Eo samples were hypermethylated at the RUNX3 promoter region, whereas only 34% of the other AML subtypes were hypermethylated. We also evaluated DNA methylation of RUNX1 and RUNX2 in a subgroup of these samples (66 samples for RUNX1 and 72 for RUNX2) and found that, as in cell lines, these genes are almost universally unmethylated; with the exception of a single AML case, all studied samples presented no promoter methylation. As support of functional outcome, hypermethylation of RUNX3 was correlated with both lower levels of mRNA and protein, as confirmed by qRT-PCR and immunohistochemistry analysis in cell lines and patient samples, and treatment with the DNA demethylating agent Decitabine resulted in mRNA re-expression of RUNX3 concomitantly with decreased promoter methylation. Finally, we compared clinicopathological features of patients with and without RUNX3 methylation. In this analysis, only non-M4Eo AML cases were compared because of the small number of non-methylated patients in the M4Eo group. Differences were found neither for blood counts nor for overall survival probability. However, relapse-free survival was significantly better for the unmethylated group (p=0.016). In summary, we showed that promoter methylation of the RUNX3 gene and down regulation of RUNX3 expression occurs almost universally in M4Eo/inversion 16 AMLs, and that in cell lines, RUNX3 repression can be reversed by treatment with the hypomethylating agent decitabine. These results suggest that silencing of RUNX3 is likely an important target in CBF leukemia and that future studies should be dedicated to further characterize the role of RUNX3 in inversion 16 AML and its predictive value of relapse-free survival in AML. Disclosures No relevant conflicts of interest to declare.

The BTK Inhibitor Ibrutinib Blocks SDF1/CXCR4 Mediated Migration of Acute Myeloid Leukemia Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 915-915
Author(s):  
Stuart A Rushworth ◽  
Lyubov Zaitseva ◽  
Megan Y Murray ◽  
Matthew J Lawes ◽  
David J MacEwan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Cell Trafficking ◽  
Acute Myeloid

Abstract Introduction Despite recent significant progress in the understanding of the biology of acute myeloid leukemia (AML) the clinical outcomes for the majority of patients diagnosed with AML presently remain poor. Consequently, there is an urgent need to identify pharmacological strategies in AML, which are not only effective but can be tolerated by the older, less well patient. Recently our group and others have shown that there is high Bruton’s Tyrosine Kinase (BTK) phosphorylation and RNA expression in AML. Moreover, our recent study described for the first time that ibrutinib and BTK-targeted RNA interference reduced factor-induced proliferation of both AML cell lines and primary AML blasts, as well as reducing AML blast adhesion to bone marrow stromal cells. Inhibition of BTK has been shown to regulate chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma cell migration by inhibiting SDF1 (stromal derived factor 1) induced CXCR4 regulated cell trafficking. Here we report that in human AML ibrutinib in addition functions in a similar way to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. Methods To investigate the role of BTK in regulating AML migration we used both pharmacological inhibitor ibrutinib and genetic knockdown using a lentivirus mediated BTK targeted miRNA in primary AML blasts and AML cell lines. We examined migration of AML blasts and AML cells to SDF-1 using Transwell permeable plates with 8.0µM pores. Western blotting was used to examine the role of SDF-1 in regulating BTK, AKT and MAPK activation in primary AML blasts. Results We initially examined the expression of CXCR4 in human AML cell lines and found that 4/4 cell lines were positive for CXCR4 expression. Next we examined the effects of ibrutinib on the migration of the AML cell lines U937, MV4-11, HL60 and THP-1 in response to SDF1. We found that ibrutinib can inhibit the migration of all AML cell lines tested. We tested the in-vitro activity of ibrutinib on SDF-1 induced migration in a spectrum of primary AML blasts from a wide age spectrum of adult patients and across a range of WHO AML subclasses and found that ibrutinib significantly inhibits primary AML blast migration (n=12). Next we found that ibrutinib can inhibit SDF-1 induced BTK phosphorylation and downstream MAPK and AKT signalling in primary AML blast. Finally to eliminate the problems associated with off target ibrutinib activity we evaluated migration of AML cells lines using genetic inhibition of BTK. The introduction of BTK-specific miRNA dramatically inhibited the expression of BTK in THP-1 and HL60 and reduced SDF1 mediated migration confirming that BTK is involved in regulating AML migration in response to SDF1. Conclusions These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL. Disclosures No relevant conflicts of interest to declare.

Differences in Expression Patterns of DNMTs and TSG Proteins in Lymphoid Tissue Section Play an Important Role in Their Association

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2657-2657
Author(s):  
Lobna Alkebsi ◽  
Hiroshi Handa ◽  
Kenichi Tahara ◽  
Hiroaki Shimizu ◽  
Takuma Ishizaki ◽  
...  
Keyword(s):  
B Cells ◽  
Protein Expression ◽  
Mrna Expression ◽  
Lymphoid Tissue ◽  
Methylation Status ◽  
Lymphoid Tissues ◽  
Expression Levels ◽  
Protein Expressions ◽  
Mrna Expression Levels ◽  
E Cadherin

Abstract In situ, patterns of expression of DNMTs (DNA methytransferases) in normal reactive tonsillar tissue have been examined. Difference in pattering of expression of DNMTs and TSG (Tumor suppressor genes) proteins in lymphoid tissue section is an important question in relation to their association with each other as well as relationship to mRNA gene expression level. In order to examine this issue, we examined DNMTs and TSG proteins expression by immunohistochemistry in sections of paraffin-embedded specimens obtained from 33 subjects of lymphoma and 16 subjects of Non-malignant tissues after receiving written informed consent. The specimens were stained with anti-DNMTs (DNMT1, DNMT3A and DNMT3B) and anti-TSG (E-cadherin, H-cadherin and ADAMTS18) antibodies. In addition, using fresh-frozen optimal cutting temperature (OCT) compound-embedded tissue specimens before any treatment, we examined mRNA expression levels and promoter methylation status of E-cadherin (CDH1), H-cadherin (CDH13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS18) using quantitative real-time PCR (qRT-PCR) and methylation-specific PCR (MSP), respectively. The expression of nuclear DNMTs proteins (DNMT1 and 3A) in lymphoma section was observed in [17/33 (51%); 27/33 (81%)], whereas in non-malignant tissues was [14/16 (87.5%); 13/16 (81%)], respectively. The DNMT3B protein expression was not detected in our tissue samples, which might be explained by the fact that DNMT3B characterized by alternative splicing as shown previously. Membrane proteins (E-cadherin, H-cadherin and ADAMTS18) showed low expression [12/33 (36%); 10/33 (30%); 6/33 (18%), respectively], when compared to non-malignant tissue sections [12/16 (75%); 7/16 (43%); 8/16 (50%), respectively]. The expression levels of CDH1, CDH13 and ADAMTS18 mRNAs were non-significantly reduced in their corresponding protein negative expression compared to the levels in cases with positive protein expression (p =0.112, p =0.378, p =0.077, respectively). We could not find any correlation between mRNA/protein expression levels of DNMTs and the methylation status of CDH1, CDH13 and ADAMTS18. Importantly, by immunostaining especially in non-malignant lymphoid tissues, we found that DNMT1 was highly detected in germinal center B cells (GC B cells) with gradual decrease or no expression in the mantle, marginal, interfollicular and T cells zones. Whereas DNMT3A was preferentially and scattered like expressed in the cells of the surrounding zones out of the germinal centers. Furthermore, E-cadherin, H-cadherin and ADAMTS18 proteins expression were detected on the cell surface membrane of the cells outside the GC but at rates somehow more than those cells inside the GC (Fig. 1). This is supported by the significant association observed between the frequency of DNMT3A with both E-cadherin and ADAMTS18, protein expressions (Chi square: p <0.05), while no association with H-cadherin protein expression. In addition, DNMT1 protein expression did not show significant association with the protein expressions of E-cadherin, H-cadherin and ADAMTS18. Moreover, the mRNA expression levels of DNMT3A and 3B showed high significant levels (p <0.05) in cases with negative protein expressions of both E-cadherin and ADAMTS18 when compared to cases with positive protein expressions (Fig. 2A and C). The DNMT1 mRNA expression level did not show any significant difference between the negative and positive protein expressions of E-cadherin, H-cadherin and ADAMTS18 (Fig. 2B). Furthermore, there was no significant association between the mRNA levels of DNMTs and H-cadherin protein expression. Expression of H-cadherin protein was frequently observed in the endothelial venules and trabeculae of the lymphoid tissues (Fig. 1) which might cause of its lack of association with both DNMT1 and DNMT3A. In conclusion, these results indicate that as a result of differences in pattering of DNMTs and TSG protein expressions detected in lymphoid tissues by immunohistochemistry staining, it might be one of the reasons of the association with each other and their mRNA expression levels across the spectrum of lymphomas and non-malignant lymphoid tissues. Disclosures No relevant conflicts of interest to declare.

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