Gene Summary

Gene:TET2; tet methylcytosine dioxygenase 2
Aliases: MDS, KIAA1546
Summary:The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. Two variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:methylcytosine dioxygenase TET2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (7)

Cancer Overview

TET2 is a tumor supressor and mutations of the gene are seen in myeloid malignancies and other hematological disorders. The TET family of proteins play a role in DNA modification, through the oxidation of methyl-cytosine, and in normal and malignant development.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Biomarkers, Tumor
  • Chronic Myelomonocytic Leukemia
  • Rats, Wistar
  • Leukemic Gene Expression Regulation
  • Cell Proliferation
  • DNA-Binding Proteins
  • DNA Methylation
  • DNA Mutational Analysis
  • Cancer Gene Expression Regulation
  • Haematological Malignancies
  • Disease Progression
  • Acute Myeloid Leukaemia
  • Neoplastic Cell Transformation
  • TET2
  • Chronic Myelogenous Leukemia
  • Testis
  • Cytosine
  • Myeloproliferative Disorders
  • Mutation
  • Genetic Predisposition
  • Adolescents
  • Epigenetics
  • Tandem Mass Spectrometry
  • Hematopoietic Stem Cells
  • Mixed Function Oxygenases
  • Chromosome 4
  • Gene Expression Profiling
  • 5-Methylcytosine
  • High-Throughput Nucleotide Sequencing
  • Myelodysplastic Syndromes
  • Neoplasm Proteins
  • Dioxygenases
  • Transcription
  • DNA (Cytosine-5-)-Methyltransferases
  • Protein Processing, Post-Translational
  • Risk Assessment
  • Nuclear Proteins
  • Single Nucleotide Polymorphism
  • Messenger RNA
  • Case-Control Studies
  • Hematopoiesis
  • Isocitrate Dehydrogenase
  • Disease-Free Survival
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TET2 (cancer-related)

Makishima H
[Genomic aberrations in myelodysplastic syndromes and related disorders].
Rinsho Ketsueki. 2019; 60(6):600-609 [PubMed] Related Publications
Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous myeloid neoplasms that frequently evolve into secondary acute myeloid leukemia (sAML). Recent progress in next-generation sequencing technologies has allowed us to discover frequent mutations throughout the coding regions of MDS, MDS/MPN, and sAML, subsequently providing information on more than 60 driver genes in these diseases. As shown by many study groups recently, such driver mutations are acquired in a gene-specific fashion. DDX41 and SAMD9/SAMD9L mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A, TET2, and ASXL1 mutations are detected as age-related clonal hematopoiesis and supposed to be a risk factor for hematological neoplasms. Recent reports on MDS have shown that mutations in genes such as NRAS and FLT3, designated as Type I genes, were significantly associated with leukemic evolution. Another type (Type II) of genes, including RUNX1 and GATA2, has been shown to be related to the progression from low-risk to high-risk MDS. These driver mutations are significantly concomitant during disease progression. Overall, various types of driver mutations are sequentially acquired in MDS, accounting for the heterogeneity of these disorders.

Zhou F, Chao H, Lu X, et al.
[Characterizing the molecular cytogenetics in acute monocytic leukemia].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019; 36(6):556-560 [PubMed] Related Publications
OBJECTIVE: To characterize the molecular genetics of 81 patients with acute monocytic leukemia (AML).
METHODS: Fluorescence in situ hybridization (FISH) was employed to detect MLL gene rearrangements. Combined mutations of 17 genes were detected by DNA-based PCR and Sanger sequencing.
RESULTS: Sixty seven patients were found to harbor at least one mutation. The most commonly mutated gene was NPM1 (n=18), which was followed by FLT3-ITD (n=16), NRAS (n=16), DNMT3A (n=15), TET2 (n=12), RUNX1 (n=11) and KRAS (n=9). Based on the functions of mutated genes, the most frequently involved genes were those involved in DNA methylation (38.27%), tyrosine kinase receptor signaling (32.1%), transcription regulation (28.4%), and RAS pathway (24.7%). Single gene mutation predominated in patient with cytogenetic abnormalities, while coexistence of 2 mutations have predominated in patient with normal cytogenetic findings. Stratified by cytogenetic findings, patients with single gene mutations (intermediate-risk group) had significantly higher complete remission (CR) rates than those with ≥2 gene mutations (unfavorable-risk group) (91.7% vs. 57.6% , 87.5% vs. 25.0%, P =0.0319, 0.0117, respectively).
CONCLUSION: Over 80% of AML patients were found to harbor at least one mutation. Their clinical phenotype and prognosis may be impacted by the synergy of MLL gene rearrangement and multiple mutations. For patients under the same risk stratification, the number of mutations is reversely correlated with the CR rate.

Wang P, Yan Y, Yu W, Zhang H
Role of ten-eleven translocation proteins and 5-hydroxymethylcytosine in hepatocellular carcinoma.
Cell Prolif. 2019; 52(4):e12626 [PubMed] Related Publications
In mammals, methylation of the 5th position of cytosine (5mC) seems to be a major epigenetic modification of DNA. This process can be reversed (resulting in cytosine) with high efficiency by dioxygenases of the ten-eleven translocation (TET) family, which perform oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine. It has been demonstrated that these 5mC oxidation derivatives are in a dynamic state and have pivotal regulatory functions. Here, we comprehensively summarized the recent research progress in the understanding of the physiological functions of the TET proteins and their mechanisms of regulation of DNA methylation and transcription. Among the three TET genes, TET1 and TET2 expression levels have frequently been shown to be low in hepatocellular carcinoma (HCC) tissues and received most attention. The modulation of TET1 also correlates with microRNAs in a post-transcriptional regulatory process. Additionally, recent studies revealed that global genomic 5hmC levels are down-regulated in HCC tissues and cell lines. Combined with the reported results, identification of 5hmC signatures in HCC tissues and in circulating cell-free DNA will certainly contribute to early detection and should help to design therapeutic strategies against HCC. 5hmC might also be a novel prognostic biomarker of HCC. Thus, a detailed understanding of the molecular mechanisms resulting in the premalignant and aggressive transformation of TET proteins and cells with 5hmC disruption might help to develop novel epigenetic therapies for HCC.

Wang R, Gao X, Yu L
The prognostic impact of tet oncogene family member 2 mutations in patients with acute myeloid leukemia: a systematic-review and meta-analysis.
BMC Cancer. 2019; 19(1):389 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The impact of Tet oncogene family member 2 (TET2) mutations on the prognosis of acute myeloid leukemia (AML) is still controversial. A meta analysis is needed in order to assess the prognostic significance of TET2 mutation in AML.
METHODS: Five databases including PubMed, Cochrane, EMBase, China National Knowledge Internet (CNKI) and Wanfang database were retrieved to search studies that investigated the correlation between TET2 mutations and outcomes of AML patients. Pooled hazard ratios (HRs) and odds ratios (ORs) were used to assess the effects of TET2 mutations.
RESULTS: Sixteen studies were included. TET2 mutation was an unfavorable prognostic factor for overall survival (OS: HR = 1.386; P < 0.001) and event-free survival (EFS: HR = 1.594; P = 0.002) in patients with AML. For patients under 65 years of age, TET2 mutation predicted an inferior OS (HR = 1.310, P = 0.051) and EFS (HR = 1.429, P = 0.027). For patients with intermediate-risk cytogenetics (IR-AML), mutant TET2 had a significant association with adverse OS (HR = 0.474; P < 0.001). For patients with normal cytogenetics (CN-AML), mutant TET2 also conferred adverse OS (HR = 1.425; P < 0.001) and EFS (HR = 1.450, P < 0.001). Further, among patients with CN-AML, mutant TET2 was associated with inferior OS (HR = 2.034, P < 0.001) and EFS (HR = 2.140, P < 0.001) in the ELN favorable-risk subgroup and an inferior EFS (HR = 1.487; P < 0.001) in the ELN intermediate-Isubgroup. With respect to treatment outcome, TET2 mutation predicted a significantly lower rate of complete remission (CR) in cases with ELN favorable-risk cytogenetics (OR = 0.460, P = 0.011).
CONCLUSIONS: TET2 mutation had adverse impacts on survival and treatment response in AML patients and will contribute to risk-stratification, prognosis prediction and therapy guidance.

Kubota S, Tokunaga K, Umezu T, et al.
Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm.
Nat Commun. 2019; 10(1):1653 [PubMed] Free Access to Full Article Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.

Kaasinen E, Kuismin O, Rajamäki K, et al.
Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.
Nat Commun. 2019; 10(1):1252 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

Ren S, Xu Y
AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma.
Cancer Sci. 2019; 110(5):1621-1632 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNAs (lncRNAs) are crucial regulators in various malignancies including glioblastoma multiforme (GBM). In the present study, we screened out a new lncRNA, AC016405.3, through a previous genome-wide lncRNA microarray analysis in GBM. It showed that AC016405.3 was downregulated in GBM tissue specimens and cell lines, and it also illustrated that the downregulated AC016405.3 was closely correlated with several aggressive features of patients with GBM. Functionally, we found that overexpression of AC016405.3 suppressed GBM cells' proliferation and metastasis using a gain of function experiment. We further showed that microRNA (miR)-19a-5p, a carcinogenic miRNA, was a downstream miRNA of AC016405.3. AC016405.3 was revealed as a target of miR-19a-5p, and overexpression of miR-19a-5p reversed the inhibitive effect of AC016405.3 on GBM cell proliferation and metastasis. Furthermore, a novel downstream gene of miR-19a-5p, TET2, was identified through a constructed microarray analysis. We showed that TET2 was downregulated in GBM and was involved in miR-19a-5p-mediated proliferation and metastasis by directly being targeted. Finally, through a western blot assay and a series of functional CCK-8 and metastatic assays, we showed that AC016405.3 suppressed proliferation and metastasis through modulation of TET2 by sponging of miR-19a-5p in GBM cells. In summary, the findings of the current study identified a novel lncRNA and illustrated that AC016405.3, acting as an anti-oncogene, suppressed GBM cell proliferation and metastasis by regulating TET through miR-19a-5p sponging. Our present study might provide a new axis in the molecular treatment of GBM.

Rasmussen KD, Berest I, Keβler S, et al.
TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells.
Genome Res. 2019; 29(4):564-575 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The epigenetic regulator

Sun J, Zhang J, Wang Y, et al.
A Pilot Study of Aberrant CpG Island Hypermethylation of
Int J Med Sci. 2019; 16(2):324-330 [PubMed] Article available free on PMC after 01/10/2019 Related Publications

Zhang H, Savage S, Schultz AR, et al.
Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.
Nat Commun. 2019; 10(1):244 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

Sukegawa S, Sakata-Yanagimoto M, Matsuoka R, et al.
[Blastic plasmacytoid dendritic cell neoplasm accompanied by chronic myelomonocytic leukemia successfully treated with azacitidine].
Rinsho Ketsueki. 2018; 59(12):2567-2573 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease that develops with a skin lesion and is often accompanied by leukemic transformation. The normal counterparts of BPDCN tumor cells are progenitors of plasmacytoid dendritic cells, whereas the origins are thought to be hematopoietic stem cells. Approximately 10%-20% of BPDCN patients develop other hematologic malignancies, including chronic myelomonocytic leukemia (CMML). Mutations in epigenetic regulators are frequently observed in both BPDCN and CMML tumors. Azacitidine, a drug that targets epigenetic dysregulation, is known to be an effective treatment for CMML. However, it has been used in few BPDCN patients. Here, we report a BPDCN patient with skin lesions, bone marrow infiltration, and lymphadenopathy. CMML also developed during the course of BPDCN. Azacitidine had positive effects on CMML; however, BPDCN aggressively relapsed during treatment. Two TET2 mutations were found in both BPDCN and CMML tumors; one of which was commonly identified in both tumors.

Kakkassery V, Jünemann AM, Scheef BO, et al.
[New molecular pathological strategies for malignant iris tumors].
Ophthalmologe. 2019; 116(4):324-331 [PubMed] Related Publications
BACKGROUND: Molecular pathological research offers new chances for the diagnostic and therapeutic management of malignant iris tumors. Besides immunohistological and polymerase chain reaction analyses further techniques, such as multiplex ligation-dependent probe amplification, microsatellite analyses and next-generation sequencing are able to detect various mutations in the tumor genome.
OBJECTIVE: An up to date review of new molecular pathological strategies for malignant iris tumors was carried out.
METHODS: This article provides a review of the recent literature based on a PubMed search and clinical experience with iris tumors.
RESULTS: The diagnostic characteristics and targeted treatment options are presented, exemplified by iris melanoma and iris carcinoma metastases. In iris melanomas, mutations in the GNA11 and GNAQ genes (in approximately 85% of the cases) seem to be important. Furthermore, the monosomy-3 status should be investigated in these tumors. In iris lymphomas, molecular pathological analyses are essential for an exact diagnosis. Detection of mutations in MYD88, BRAF, KLF2, ID3, TCF3, STAT3, RHo, TET2, IDH2, CXCR4, CD79B and DNMT3A are helpful. In particular, the detection of the CD20 antigen is of therapeutic relevance because this lymphoma subgroup responds well to rituximab, a CD20 antibody treatment. In iris carcinoma metastases, investigations for mutations are helpful because then a targeted treatment seems to be possible.
CONCLUSION: Molecular pathological analyses will become essential in the future management of iris tumors because they play a key role towards a personalized treatment approach.

Furuya K, Ikura M, Ikura T
Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis.
J Biochem. 2019; 165(4):297-299 [PubMed] Related Publications
Epigenetic systems are organized by different types of modifications on histones and DNA. To determine how epigenetic systems can produce variable, yet stable cellular outcomes, understanding the collaboration between these modifications is the key. A recent study by Yamagata and Kobayashi revealed the direct interplay between the regulation of two epigenetic modifications: DNA de-methylation by TET2 and histone H3-K36 methylation. Mechanistically, this finding could explain how cells are protected from oncogenesis by maintaining the integrity of active transcription. The recent identification of epigenetic modifier mutations in leukaemia suggested that it is not just the turning 'on' and 'off' of particular transcriptional events that causes disease occurrence, but rather it is the aberration in epigenetic regulation, i.e. the timing and duration of the activation/inactivation of these transcripts. Thus, a comprehensive understanding of how epigenetic interplays tune transcription will be the new perspective for disease research.

Iqbal J, Amador C, McKeithan TW, Chan WC
Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma.
Cancer Treat Res. 2019; 176:31-68 [PubMed] Related Publications
Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

Song J, Moscinski L, Zhang H, et al.
Cancer Genomics Proteomics. 2019 Jan-Feb; 16(1):91-98 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Mutations in splicing factor 3b subunit 1 (SF3B1) have been reported to be associated with a favorable prognosis, while the prognostic impact of tet methylcytosine dioxygenase 2 (TET2) mutations is still controversial. The clinical significance of combined SF3B1 and TET2 mutation is even more uncertain. In this study, the clinical consequences of concurrent double SF3B1/TET2 mutation were compared with isolated SF3B1 or TET2 mutation.
MATERIALS AND METHODS: The demographics, diagnosis, cytogenetic abnormalities, and overall survival time of 130 patients with isolated SF3B1 (n=48) or TET2 mutation (n=54), or double SF3B1/TET2 mutation (n=28) were compared by next-generation sequencing.
RESULTS: Patients with double mutation were found to be significantly older than patients with isolated TET2 mutation. Patients with double mutation or isolated SF3B1 mutation were less likely to be diagnosed with acute myeloid leukemia than patients with isolated TET2 mutation. Patients with myelodysplasia had a higher percentage of double or isolated SF3B1 mutation, while patients with myeloproliferative neoplasms had a higher percentage of isolated TET2 mutation. Patients with double mutation more frequently had increased ring sideroblasts similarly to patients with isolated SF3B1 mutation. The percentage of patients with normal cytogenetics or good cytogenetic abnormalities was significantly higher in patients with double mutation than those with isolated mutation. Finally, in patients with myelodysplasia and normal cytogenetics, the median survival time in those with double mutation was significantly longer than in those with isolated SF3B1 mutation, even though the overall survival curve was not statistically significant.
CONCLUSION: TET2 mutation appeared not to have additional effects when combined with SF3B1, and patients with double mutation appeared to have at least as, good as or even better prognosis than patients with isolated mutation.

Potter N, Miraki-Moud F, Ermini L, et al.
Single cell analysis of clonal architecture in acute myeloid leukaemia.
Leukemia. 2019; 33(5):1113-1123 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34

Steensma DP
Clinical consequences of clonal hematopoiesis of indeterminate potential.
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):264-269 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as

Dumas PY, Mansier O, Prouzet-Mauleon V, et al.
MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms.
BMC Cancer. 2018; 18(1):1098 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients.
METHODS: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34
RESULTS: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors.
CONCLUSIONS: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.

Menter T, Lundberg P, Wenzel F, et al.
RUNX1 Mutations Can Lead to Aberrant Expression of CD79a and PAX5 in Acute Myelogenous Leukemias: A Potential Diagnostic Pitfall.
Pathobiology. 2019; 86(2-3):162-166 [PubMed] Related Publications
BACKGROUND: RUNX1 is a crucial transcription factor for hematological stem cells and well-known for its association with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Besides the translocation t(8; 21) that leads to the RUNX1-RUNX1T1 fusion, somatic mutations of RUNX1 have been discovered.
METHODS: Four bone marrow trephine biopsies of patients with CD79a-positive and/or PAX5-positive acute leukemias were investigated by immunohistochemistry (IHC), karyotyping, and next-generation sequencing-based genetic analysis. Data were then compared to a historical collective of AML (n = 42) and 42 cases of AML newly diagnosed at our institution between June 2017 and May 2018.
RESULTS: We report on 4 cases of acute leukemia with an equivocal immunophenotype showing expression of CD79a and/or PAX5, which led to a preliminary histopathologic classification as probable ALL/unclassifiable acute leukemia. All cases were positive for CD34 and TdT but negative for several myeloid markers on IHC. Mutational analysis revealed point mutations and indels of RUNX1 and further mutations typical for AML such as TET2, DNMT3A, and SRSF2, and 2 cases had tetrasomy 13 characteristic of RUNX1 mutant AML.
CONCLUSION: Aberrant CD79a and/or PAX5 expression can be found in AML cases with RUNX1 mutations even without the translocation t(8; 21). Our series shows the expression of CD79a and PAX5 to be a potential pitfall in the classification of RUNX1 mutant acute leukemia.

Zhang J, Tan P, Guo L, et al.
p53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance.
Oncogene. 2019; 38(11):1905-1919 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Tumor cells with p53 inactivation frequently exhibit chemotherapy resistance, which poses a long-standing challenge to cancer treatment. Here we unveiled a previously unrecognized role of TET2 in mediating p53-loss induced chemotherapy resistance in colon cancer. Deletion of TET2 in p53-null colon cancer cells enhanced DNA damage and restored chemotherapy sensitivity. By taking a two-pronged approach that combined pharmacological inhibition with genetic depletion, we discovered that p53 destabilized TET2 at the protein level by promoting its autophagic degradation. At the molecular level, we further revealed a physical association between TET2 and p53 that facilitated the nucleoplasmic shuttling of TET2, as well as its recruitment to the autophagosome for degradation. Our study has unveiled a functional interplay between TET2 and p53 during anti-cancer therapy. Our findings establish the rationale for targeting TET2 to overcome chemotherapy resistance associated with mutant p53 tumors.

Fukunaga T, Fujita Y, Kishima H, Yamashita T
Methylation dependent down-regulation of G0S2 leads to suppression of invasion and improved prognosis of IDH1-mutant glioma.
PLoS One. 2018; 13(11):e0206552 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Isocitrate dehydrogenase (IDH) mutations are a prognostic factor in diffuse glioma. However, the mechanism by which these mutations improve prognosis are not clear. In a subset of IDH-mutant glioma, remodeling of the methylome results in the glioma-CpG island methylator phenotype (G-CIMP) and transcriptional reorganization. In this study, we focus on G0/G1 switch 2 (G0S2), which is highly downregulated in G-CIMP glioma. We found that G0S2 expression tended to increase as the WHO grade increased, and G0S2 knockdown inhibited glioma invasion. Additionally, we revealed that the overexpression of the DNA demethylase Ten-eleven translocation 2 (TET2) in IDH1-plasmid transfected glioblastoma multiforme (GBM) cells restored G0S2 expression. These results indicate that G0S2 is epigenetically silenced in IDH1-mutant glioma. In addition, the stereotactic delivery of glioma cells with decreased G0S2 expression in the mouse brain resulted in prolonged survival. The Cancer Genome Atlas (TCGA) analysis also indicated that survival is longer in the lower G0S2 expression group than in the higher G0S2 expression group. Moreover, G0S2 expression was higher in recurrent tumor specimens than at the initial diagnosis in the same patient. These results provide one explanation for the improved survival in IDH1-mutant glioma as well as a new epigenetic target for glioma treatment.

Khoury JD
Blastic Plasmacytoid Dendritic Cell Neoplasm.
Curr Hematol Malig Rep. 2018; 13(6):477-483 [PubMed] Related Publications
PURPOSE OF REVIEW: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy derived from plasmacyoid dendritic cells whose biology, clinical features, and treatment options are increasingly better understood.
RECENT FINDINGS: TCF4 is a master regulator that drives donwstream transcriptional programs in BPDCN. In turn, TCF4 activity is dependent on the bromodomain and extra-terminal domain (BET) protein BRD4 whose inhibition provides a promising therapeutic vulnerability. Notably, TCF4 expression is a highly sensitive marker for BPDCN and augments diagnostic specificity alongside CD4, CD56, CD123, and TCL1. The gene expression profile of BPDCN is characterized by aberrant NF-kappaB pathway activation, while its genomic landscape is dominated by structural chromosomal alterations involving ETV6, MYC, and NR3C1, as well as mutations in epigenetic regulators particularly TET2. Advances in elucidating the biological characteristics of BPDCN are resulting in a more refined diagnostic approach and are opening novel therapeutic avenues for patients with this disease.

Fei DL, Zhen T, Durham B, et al.
Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene
Proc Natl Acad Sci U S A. 2018; 115(44):E10437-E10446 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of

Shiba N
[Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia].
Rinsho Ketsueki. 2018; 59(10):2260-2267 [PubMed] Related Publications
The pathogenesis of acute myeloid leukemia (AML) is heterogeneous and caused by various chromosomal aberrations, gene mutations or epigenetic modifications, and deregulated or overregulated gene expression, leading to increased proliferation and decreased hematopoietic progenitor cell differentiation. Although most of these aberrations are correlated with prognosis, accurate risk stratification remains challenging even after incorporating these molecular markers. The development of analytical techniques using microarrays and massive parallel sequencing has identified some gene mutations in adult AML, including DNMT3A and TET2 mutations. However, these mutations are rare in pediatric AML cases. However, a considerable amount of gene fusions was detected in pediatric AML, indicating that a different pathogenesis may exist between adult and pediatric AML. To facilitate genome-based treatment, we should revise the risk classification of AML more appropriately, adopting mutations of NPM1, biallelic CEBPA, and KMT2A-PTD and novel gene fusions, including CBFA2T3-GLIS2 and NUP98-JARID1A. Furthermore, new promising molecular-targeted drugs without side effects are recommended to improve the prognosis of AML.

Yokoyama K, Shimizu E, Yokoyama N, et al.
Cell-lineage level-targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes.
Blood Adv. 2018; 2(19):2513-2521 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Acute myeloid leukemia (AML) is a clonal myeloid neoplasm that typically arises de novo; however, some cases evolve from a preleukemic state, such as myelodysplastic syndrome (MDS). Such secondary AMLs and those with typical MDS-related clinical features are known as AMLs with myelodysplasia-related changes (AML-MRC). Because patients with AML-MRC have poor prognosis, more accurate diagnostic approaches are required. In this study, we performed targeted sequencing of 54 genes in 3 cell populations (granulocyte, blast, and T-cell fractions) using samples from 13 patients with MDS, 16 patients with clinically diagnosed AML-MRC, 4 patients with suspected AML-MRC but clinically diagnosed as AML not otherwise specified (AML-NOS), and 11 patients with de novo AML. We found that overlapping mutations, defined as those shared at least by the blast and granulocyte fractions, were significantly enriched in patients with MDS and AML-MRC, including those with suspected AML-MRC, indicating a substantial history of clonal hematopoiesis. In contrast, blast-specific nonoverlapping mutations were significantly enriched in patients with de novo AML. Furthermore, the presence of overlapping mutations, excluding

Fiedler EC, Shaw RJ
AMPK Regulates the Epigenome through Phosphorylation of TET2.
Cell Metab. 2018; 28(4):534-536 [PubMed] Related Publications
Emerging evidence suggests that changes to cellular metabolism can regulate epigenetic modifications to alter gene expression. Recently in Nature, Wu et al. show that the metabolic regulator AMPK can phosphorylate and thus stabilize the epigenetic modifying enzyme TET2, defining a novel signaling link between metabolism and the epigenome.

Döhner H, Dolnik A, Tang L, et al.
Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care.
Leukemia. 2018; 32(12):2546-2557 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m

Tara S, Isshiki Y, Nakajima-Takagi Y, et al.
Blood. 2018; 132(23):2470-2483 [PubMed] Article available free on PMC after 06/12/2019 Related Publications

Montes-Moreno S, Routbort MJ, Lohman EJ, et al.
Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era.
PLoS One. 2018; 13(9):e0204218 [PubMed] Article available free on PMC after 06/12/2019 Related Publications
ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease.

Chen YJ, Huang CH, Shi YJ, et al.
The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.
Toxicol Appl Pharmacol. 2018; 358:43-55 [PubMed] Related Publications
Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation. In addition, ATO-treated U937 cells showed ROS-mediated inhibition of TET2 transcription, leading to downregulation of FOXP3 expression and in turn, suppression of FOXP3-mediated activation of Lyn and Akt. Overexpression of FOXP3 or Lyn minimized the suppressive effect of ATO on Akt activation and MCL1 expression. Promoter luciferase activity and chromatin immunoprecipitation assays revealed the crucial role of Akt-mediated CREB phosphorylation in MCL1 transcription. Further, ATO-induced Akt inactivation promoted GSK3β-mediated degradation of MCL1. Transfection of constitutively active Akt expression abrogated ATO-induced MCL1 downregulation. MCL1 overexpression lessened the ATO-induced depolarization of mitochondrial membrane and increased the viability of ATO-treated cells. Thus, our data suggest that ATO induces mitochondria-mediated apoptosis in U937 cells through its suppressive effect on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 transcription and protein stabilization. Our findings also indicate that the same pathway underlies ATO-induced death in human leukemia HL-60 cells.

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