TET2 expression level and 5-hydroxymethylcytosine are decreased in refractory cytopenia of childhood

Coutinho, Diego F.; Monte-Mór, Bárbara; Vianna, Danielle T.; Rouxinol, Soraia; Batalha, Anna Beatriz W.; Bueno, Ana Paula Silva; Boulhosa, Alice M.; Fernández, Teresa; Pombo‐de‐Oliveira, Maria S.; Gutiyama, Luciana M.; Abdelhay, Eliana; Zalcberg, Ilana

doi:10.1016/j.leukres.2015.07.005

Cited by 22 publications

(21 citation statements)

References 34 publications

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“…The percentage of 5-hmC was decreased in childhood refractory cytopenia as well as TET2 expression. This decreased expression was not associated with the presence of mutations but was correlated with an increase in microRNA-22, which may regulate the enzyme [55]. Another study suggested that loss of %5-hmC may be due to simple nuclear exclusion of the oxidases [56].…”

Section: Discussionmentioning

confidence: 99%

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance

et al. 2016

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BackgroundChronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries, characterized by a heterogeneous clinical course. Although genetic studies have identified chromosomal aberrations or specific mutations, epigenetic changes have been poorly characterized in CLL.MethodsWe assessed ten-eleven translocations (TET) 1, 2, and 3, isocitrate dehydrogenase (IDH) 1, and 2 messenger RNA (mRNA) expression using real-time PCR on purified leukemic B cells from 214 CLL patients (median follow-up = 75 months, range 1–380), normal peripheral blood B cells (n = 20), and umbilical cord blood B cells (n = 21). The microenvironment influence was assessed after 24 h co-culture of CLL cells with bone marrow mesenchymal stromal cells (BMSC). Finally, 5-hydroxymethylcytosine level (%5-hmC) was assessed by ELISA in CLL cells alone or with microenvironment stimuli.ResultsTET 1 and 3 and IDH2 were decreased in CLL cells compared with healthy B cells (P = 0.0221, 0.0013, <0.0001, respectively), while IDH1 was overexpressed (P = 0.0037). TET2 and IDH1 were significantly correlated with treatment-free survival (TFS); patients with high TET2/IDH1 expression had a higher median TFS (111 months) than patients with low expression (78 months, P = 0.0071/0.0123). Moreover, TET1 expression decreased (P = 0.0371), while TET3 and IDH2 expression increased (P = 0.0273/0.0039) in co-cultures. However, %5-hmC was not correlated with clinical data and was unchanged following microenvironment stimuli.ConclusionsDespite a slight deregulation in CLL cells compared with normal B cells, we identified a significant association between TET/IDH gene expression and prognosis, suggesting that epigenetic changes could potentially be associated with disease progression. Moreover, despite an identical %5-hmC, TET gene expression was influenced by contact with BMSC confirming the crucial role of the microenvironment in CLL pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0298-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance

et al. 2016

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“…5-hmC of transcription factor binding sites commonly initiates gene expression, and the down-expression of TET often fails to activate gene transcription owing to the low level of 5-hmC (49,50). For instance, analysis of patients with refractory cytopenia of childhood revealed that the high expression of miR-22 has a closely converse relationship with the low expression of TET and 5-hmC (51). Furthermore, recent investigations have confirmed in miR-22 transgenic mice that by directly targeting TET2, not only is miR-22 against methylation of tumor suppressor miR-200 promoter, causing the downregulation of miR-200 and the initiation of EMT process and distant metastasis for breast cancer stem cells, which is closely correlated with the poor prognosis of patients (52), but also it contributes to the low levels of other 5-hmC of downstream genes, leading to self-renewal and malignant transformation of blood stem cells in these mice, which eventually undergo MDS and malignant blood diseases.…”

Section: Molecular Regulatory Mechanisms Of Mir-22 At the Genetic mentioning

confidence: 99%

Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review)

Wang

Ding

et al. 2016

International Journal of Oncology

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miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3′-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR-22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis.

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“…Meanwhile, JAK3, STAT3, and STAT5 repress miR-22 expression; thus, miR-22 provides an important link to explain how activating mutations in the JAK-STAT pathway promote cancer 14 . Additionally, increased expression of miR-22 correlates with poor survival in myelodysplastic syndrome (MDS) and leukemia 15 , and the tumor suppressor and epigenetic modifier Tet2 is a key target of miR-22 16, 17 . Patients with MDS express high miR-22 levels and HSCs over-expressing miR-22 show increased replating and repopulation capacity, indicative of more aggressive disease 17 .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

Kadmon

Landers

et al. 2017

Experimental Hematology

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MicroRNA-22 (miR-22) is a highly conserved microRNA that can regulate cell proliferation, oncogenesis, and cell maturation, especially during stress. In hematopoietic stem cells (HSCs) miR-22 has been reported to be involved in the regulation of key self-renewal factors including Tet2. Recent work demonstrates that miR-22 also participates in regulation of the interferon response, and expression profiling studies suggest that it is variably expressed at different stages in erythroid differentiation. We thus hypothesized that miR-22 regulates maturation of erythroid progenitors during stress hematopoiesis through its interaction with interferon. We compared the blood and bone marrow of wild type (WT) and miR-22-deficient mice at baseline and upon infectious challenge with systemic lymphochoriomeningitis (LCMV) virus. MiR-22-deficient mice maintained platelet counts better than WT mice during infection, but they showed significantly reduced red blood cells (RBC) and hemoglobin. Analysis of bone marrow progenitors demonstrated better overall survival and improved HSC homeostasis in infected miR-22-null mice compared to WT, attributable to a blunted interferon response to LCMV challenge in the miR-22-null mice. We found that miR-22 was exclusively expressed in stage II erythroid precursors and was downregulated upon infection in WT mice. Our results indicate that miR-22 promotes the interferon response to viral infection and that it functions at baseline as a brake to slow erythroid differentiation and maintain adequate erythroid potential. Impaired regulation of erythrogenesis in the absence of miR-22 can lead to anemia during infection.

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TET2 expression level and 5-hydroxymethylcytosine are decreased in refractory cytopenia of childhood

Cited by 22 publications

References 34 publications

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance

Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review)

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

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