High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells

Numata, Masayuki; Yener, Mehmet; Ekmekçi, Sema Sırma; Aydin, Müge; Grosveld, Gerard; Cardone, Monica; Terranova, Sabrina; Geltink, Ramon I. Klein; Özbek, Uğur; Özçelik, Emrah; Güleç, Çağrı; Anak, Sema; Karaman, Serap; Öztürk, Gülyüz; Akbiyik, Meral; Kandilci, Ayten

doi:10.1016/j.leukres.2015.05.013

Cited by 3 publications

(3 citation statements)

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“…Kandilci A. et al reported that CEBPA downregulation contributes to MN1modulated leukemogenesis, and reintroduction of CEBPA in MN1-overexpressing hematopoietic cells prevents their hyperproliferation and restores myeloid differentiation [19]. Besides, MN1 has been reported significantly upregulated in ETV6-AML1-positive B-cell acute lymphoblastic patients [20]. MN1 has also been observed to fuse with another ETS family of transcription factors gene FLI1 in acute megakaryoblastic leukemia [21].…”

Section: Discussionmentioning

confidence: 99%

Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12)

et al. 2020

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Chromosome translocation t(12;22)(p13;q12)/MN1-ETV6 and MN1 overexpression confer a subset of adverse prognostic AML but so far lack in-depth research. We focused on the clinical course and comprehensive genetic analysis of eight cases with t(12;22)(p13;q12) and one with t(12;17;22) (p13;q21;q13) to elucidate their molecular etiology and outcomes of allogeneic hemopoietic stem cell transplantation (allo-HSCT). The total incidence of t(12;22)(p13;q12) and related translocations was 0.32% in myeloid neoplasms. These patients were confirmed to have dismal prognosis when treated only with chemotherapy, and we firstly provided evidence that they can significantly benefit from timely allo-HSCT. Five cases were MN1-ETV6 positive, and a novel MN1-STAT3 fusion was identified in the patient with triadic translocation. Significant MN1 overexpression was observed in all three MN1-fusion-negative cases. Genetic analysis highlighted the evidence of an ectopic super-enhancer associated orchestrated mechanism of MN1 overexpression and ETV6 haploinsufficiency in t(12;22) (p13;q12) myeloid neoplasms, rather than the conventional thought of MN1-ETV6 fusion formation. We also disclosed the high concomitance of trisomy 8 and 531 Kbps focal 8q duplication in t(12;22)(p13;q12) cases. The new perspective about this entity of disease will enlighten further research to define the mechanism of tumorigenesis and discover effective treatments for MN1-driven malignancies.

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Section: Discussionmentioning

confidence: 99%

Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12)

et al. 2020

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“…Our analysis suggests that the peripheral blood CD19 + B cells pool in JIA-U− and JIA-U+ patients display an overall remarkably similar transcriptome, also compared to controls. The differential expression analysis revealed only six differently expressed genes (DEGs) after FDR correction, which suggests that these differences are unlikely robust, but included genes such as TXNIP – related to B cell associated germinal centers in peripheral lymphoid organs ( 31 ) and MN1 , linked to colony forming activity of B cells ( 32 ). Polymorphisms (SNPs) in the HLA-DPB1 gene are associated with the susceptibility to uveitis in JIA ( 7 ), but the gene expression of HLA-DPB1 was (slightly) decreased in JIA cases either with or without uveitis compared to controls (JIA-U+, Log2[FC] = −0.33, P = 0.016; JIA-U−, Log2[FC] = −0.34, P = 0.013).…”

Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

et al. 2020

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Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

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“…More importantly, its potential relationship with leukemia, including AML, has also been described [14]. It is reported that high expression of MN1 was shown to be a predictor of poor clinical outcome in AML patients with a normal karyotype [15] and ectopic expression of MN1 in mouse bone marrow cells led to myeloid leukemia [16, 17]. Moreover, MN1 overexpression in mouse and human hematopoietic stem/progenitor cells resulted in the abnormal proliferation and arrest of myeloid differentiation [18], while suppression of MN1 in leukemia cells inhibited their proliferation [19].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of TEL-MN1 Fusion Enhances Resistance of HL-60 Cells to Idarubicin

et al. 2018

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Background: The translocation t(12; 22) (p13;q12) is a recurrent but infrequent chromosome abnormality in human myeloid malignancies. To date, the role of TEL-MN1 fusion in leukemogenic process and drug resistance is still largely unknown. Methods: In the present study, the TEL-MN1 fusion was transfected into HL-60 cells to upregulate TEL-MN1 expression via a retroviral vector. MTT assay was employed to examine cell viability and flow cytometry was performed to evaluate cell apoptosis. Idarubicin was used to treat HL-60 cells for estimating the effect of TEL-MN1 fusion on the chemotherapy resistance. Results: The results showed that overexpression of TEL-MN1 in HL-60 cells could promote cell proliferation, suggesting that TEL-MN1 may be involved in the leukemogenesis process. HL-60 cells treated with idarubicin showed a weakened cell viability, whereas TEL-MN1 overexpression attenuated the idarubicin-induced inhibition of cell viability and acceleration of cell apoptosis of HL-60 cells. Conclusion: Taken together, our results indicated that TEL-MN1 fusion is an oncogene involved in the leukemogenesis process and TEL-MN1 overexpression enhanced resistance of HL-60 cells to idarubicin, which may provide a useful tool for studying the mechanism of leukemogenesis and drug resistance.

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High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells

Cited by 3 publications

References 13 publications

Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12)

Ectopia associated MN1 fusions and aberrant activation in myeloid neoplasms with t(12;22)(p13;q12)

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Overexpression of TEL-MN1 Fusion Enhances Resistance of HL-60 Cells to Idarubicin

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