Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies

Li, Zhe; Cai, Xiaoqiang; Cai, Chen; Wang, Jiapeng; Zhang, Wenyong; Petersen, Bruce; Yang, Feng Chun; Xu, Mingjiang

doi:10.1182/blood-2010-12-325241

Cited by 585 publications

(610 citation statements)

References 29 publications

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“…Mice overexpressing miR-26a are viable and overtly normal, as are TET2 homozygous knockout mice (45). This may suggest that miR-26a and TET2 are only involved in the fine-tuning of embryogenesis and development.…”

Section: Discussionmentioning

confidence: 94%

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

Jin

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

115

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Ten eleven translocation (TET) enzymes (TET1/TET2/TET3) and thymine DNA glycosylase (TDG) play crucial roles in early embryonic and germ cell development by mediating DNA demethylation. However, the molecular mechanisms that regulate TETs/TDG expression and their role in cellular differentiation, including that of the pancreas, are not known. Here, we report that (i) TET1/2/3 and TDG can be direct targets of the microRNA miR-26a, (ii) murine TETs, especially TET2 and TDG, are down-regulated in islets during postnatal differentiation, whereas miR-26a is up-regulated, (iii) changes in 5-hydroxymethylcytosine accompany changes in TET mRNA levels, (iv) these changes in mRNA and 5-hydroxymethylcytosine are also seen in an in vitro differentiation system initiated with FACS-sorted adult ductal progenitor-like cells, and (v) overexpression of miR-26a in mice increases postnatal islet cell number in vivo and endocrine/acinar colonies in vitro. These results establish a previously unknown link between miRNAs and TET expression levels, and suggest a potential role for miR-26a and TET family proteins in pancreatic cell differentiation.T en eleven translocation (TET) enzymes and thymine DNA glycosylase (TDG) are implicated in active DNA demethylation (1-3). The three TET family enzymes oxidize 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC), and subsequently to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (1, 2, 4, 5). TDG, a base excision repair glycosylase, replaces 5fC and 5caC with an unmodified cytosine via DNA repair (5, 6). Despite these advances, the molecular mechanisms underlying TETs/ TDG regulation are still not known. In addition, although recent data suggest a role of TET and 5hmC in embryonic stem cells and primordial germ cells (2, 7-12), evidence for enzymatic demethylation by TET enzymes during differentiation of cells of later stages, such as the postnatal and adult stem cells of various organs including pancreas, remains very limited (13-16).MicroRNAs (miRNAs) are an abundant class of small, highly conserved noncoding RNAs that bind the 3′-untranslated regions (UTRs) of protein-coding genes to suppress gene expression. Accumulating data have demonstrated that miRNAs are critical for many developmental and cellular processes, including organogenesis and differentiation (17). However, the role of miRNAs in TET expression and active DNA demethylation remains unclear.Three major cell lineages exist in the adult pancreas-duct, acinar, and endocrine cells. The endocrine pancreas is composed of several hormone-releasing cells, including the insulin-secreting beta cells and glucagon-secreting alpha cells. Many transcription factors are known to control pancreas development (18). For example, the expression of pancreatic and duodenal homeobox 1 (Pdx1) in embryonic foregut region induces pancreas commitment (19,20), and those early progenitor cells have the potential to give rise to all three pancreatic lineages (21,22). Subsequent activation of another transcription factor, neurogenin 3 (N...

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Section: Discussionmentioning

confidence: 94%

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

Jin

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

115

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“…Notably, TET2 conditional knockout mice exhibit leukocytosis, neutrophilia, monocytosis and splenomegaly, features characteristic of human chronic myelomonocytic leukemia. [22][23][24][25] The residual levels of TET2 in our TET2 trap/trap mice may account for this difference in myeloproliferative features. However, even complete loss of TET2 results in a much milder MPN phenotype than observed in JAK2 V617F mice.…”

Section: In Bm Compartments Including Linmentioning

confidence: 99%

“…This result was consistent with the recently reported studies using adult BM cells from TET2 conditional knockout mice. [22][23][24][25] Thus, TET2 appears to function cell autonomously, with the loss of TET2 likely conferring a proliferative advantage to FL cells in vivo. The increased self-renewal activity in cells with TET2 loss-of-function mutations might be responsible for the initiation of MPN.…”

Section: In Bm Compartments Including Linmentioning

confidence: 99%

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TET2 is essential for survival and hematopoietic stem cell homeostasis

et al. 2012

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Ten-Eleven-Translocation 2 (TET2) is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) and thereby alters the epigenetic state of DNA; somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies. To study the function of TET2 in vivo, we analyzed Ayu17-449 (TET2 trap ) mice, in which a gene trap insertion in intron 2 of TET2 reduces TET2 mRNA levels to about 20% of that found in wild-type (WT) mice. TET2 trap/trap mice were born at Mendelian frequency but died at a high rate by postnatal day 3, indicating the essential role of TET2 for survival. Loss of TET2 results in an increase in the number of hematopoietic stem cells (HSCs)/progenitors in the fetal liver, and TET2 trap/trapHSCs exhibit an increased self-renewal ability in vivo. In competitive transplantation assays, TET2 trap/trap HSCs possess a competitive growth advantage over WT HSCs. These data indicate that TET2 has a critical role in survival and HSC homeostasis. (2012) 26, 2216-2223; doi:10.1038/leu.2012.94 Keywords: TET2; myeloproliferative neoplasms; tumor suppressor; animal models; hematopoietic stem cells Leukemia INTRODUCTIONMyeloproliferative neoplasms (MPNs) are characterized by an overproduction of white blood cells and are frequently associated with a somatic Janus kinase 2 (JAK2) V617F mutation that results in a constitutively active protein. [1][2][3][4] The presence of JAK2 V617F alone can cause MPN in mouse models, 5-9 but does not confer a growth advantage upon hematopoietic stem cells (HSCs). 9In female MPN patients tested for JAK2 mutations and X-chromosomal clonality, the percentage of granulocytes and platelets with a JAK2 mutation was often markedly lower than the percentage of clonal granulocytes. 10,11 In addition, JAK2-V617F-positive MPNs are frequently found in patients with JAK2-V617F-negative acute myeloid leukemia. 12 These data suggest that the MPN cells expand clonally before acquisition of a JAK2 mutation, and that the leukemic transformation shares a common clonal origin in MPN and acute myeloid leukemia.Mutations in Ten-Eleven-Translocation-2 (TET2) have also been observed in 10-20% of patients with MPN,13,14 as well as in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia, [14][15][16][17] suggesting that mutation of TET2 is a common pathogenetic event in myeloid malignancies. TET family members share a highly conserved catalytic domain, and both TET1 and TET2 catalyze the conversion of 5-methylcytosine into 5-hmC, [18][19][20] resulting in the modification of DNA. The amount of 5-hmC in DNA from patients with myeloid malignancies was lower when they possessed a TET2 mutation than when they did not, 19 suggesting that the mutant TET2 protein was defective in its enzymatic function. Recent work has shown that small hairpin RNA-mediated depletion of TET2 in murine hematopoietic precursors alters their differentiation toward monocyte/macrophage lineages in vitro, suggesting...

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“…6 We and others reported that TET2-deficient hematopoietic stem cells showed increased selfrenewal ability and exhibited a competitive growth advantage over wild-type hematopoietic stem cells. [7][8][9][10] In addition to myeloid malignancies, TET2 mutations have been detected in B-lineage and T-lineage lymphoid malignancies. [11][12][13][14][15] Of these, TET2 was most frequently mutated in angioimmunoblastic T-cell lymphomas and "Th follicular (TFH) -like" peripheral T-cell lymphomas, not otherwise specified.…”

Section: Introductionmentioning

confidence: 99%

TET2 Mutation in Adult T-Cell Leukemia/Lymphoma

Shimoda¹,

Shide²,

Kameda³

et al. 2015

J Clin Exp Hematopathol

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Loss-of-function of ten-eleven translocation-2 (TET2) is a common event in myeloid malignancies, and plays pleiotropic roles, including augmenting stem cell self-renewal and skewing hematopoietic cells to the myeloid lineage. TET2 mutation has also been reported in lymphoid malignancies; 5.7∼12% of diffuse large B-cell lymphomas and 18∼83% of angioimmunoblastic T-cell lymphomas had TET2 mutations. We investigated TET2 mutations in 22 adult T-cell leukemia/lymphoma (ATLL) patients and identified a missense mutation in 3 cases (14%). TET2 mutation occurred in a number of ATLL patients and was likely involved in their leukemogenesis.

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Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies

Cited by 585 publications

References 29 publications

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

TET2 is essential for survival and hematopoietic stem cell homeostasis

TET2 Mutation in Adult T-Cell Leukemia/Lymphoma

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