News - TET2 deletion - LARVOL VERI

1year

Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice. (PubMed, Commun Biol)

In order to gain insight on the TET mediated molecular events that safeguard T cells from aberrant proliferation we performed serial adoptive transfers of murine CD4 T cells that lack concomitantly TET2 and TET3 to fully immunocompetent congenic mice. Here we show a progressive acquisition of malignant traits upon loss of TET2 and TET3 that is characterized by loss of genomic integrity, acquisition of aneuploidy and upregulation of the protooncogene Myc.

1 year ago

Preclinical • Journal

TET2 (Tet Methylcytosine Dioxygenase 2) • CD4 (CD4 Molecule)

TET2 deletion

over1year

Diagnosis of systemic mastocytosis with cryptic deletion of TET2 and DNMT3A resulting from unbalanced translocation. (PubMed, Br J Haematol)

Classically, cytogenetic aberrations are not common except in cases of SM associated with another haematological neoplasm. We highlight here an unusual clinical presentation of SM and demonstrate the utility of advanced cytogenetic analysis (optical genome mapping, OGM) in detecting a novel cytogenetic abnormality resulting in an unusual mechanism of DNMT3A and TET2 loss of function.

over 1 year ago

Journal

KIT (KIT proto-oncogene, receptor tyrosine kinase) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

KIT mutation • KIT D816V • TET2 deletion

almost2years

Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration. (PubMed, Cell Commun Signal)

Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function.

almost 2 years ago

Journal

TET2 (Tet Methylcytosine Dioxygenase 2) • IL6 (Interleukin 6) • HGF (Hepatocyte growth factor) • TET1 (Tet Methylcytosine Dioxygenase 1)

TET2 deletion

almost2years

Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells. (PubMed, Nat Commun)

Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

almost 2 years ago

Journal

TET2 (Tet Methylcytosine Dioxygenase 2) • IL1B (Interleukin 1, beta)

TET2 deletion

2years

Brd4 Inhibition Abrogates Inflammation and Self-Renewal in a Murine Model of Tet2 Mutated Clonal Hematopoiesis (ASH 2023)

To study pharmacologic Brd4 inhibition in Tet2 KO mice, we utilized PLX51107, a structurally distinct BET inhibitor previously reported on by our laboratory...Our novel inducible double knockout mouse model of CH achieved simultaneous knockout of Brd4 and Tet2, which has never been investigated. Collectively, our data provides rationale for further pre-clinical investigation of BET inhibitors to prevent progression of Tet2 CH.

2 years ago

Preclinical

TET2 (Tet Methylcytosine Dioxygenase 2) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL18 (Interleukin 18) • BRD4 (Bromodomain Containing 4) • IL1B (Interleukin 1, beta) • NLRP3 (NLR Family Pyrin Domain Containing 3) • BRD2 (Bromodomain Containing 2) • BRD3 (Bromodomain Containing 3)

TET2 mutation • TET2 deletion

PLX51107

2years

Molecular Taxonomy of Myelodysplastic Syndromes and Its Clinical Implications (ASH 2023)

The prognostic influence of bone marrow blasts varied in the individual genetic subgroups, suggesting that the clinical impact of increased blasts depends on the genetic context. The molecular taxonomy derived in this study is clinically relevant and will inform future classification schemas.

2 years ago

Clinical

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1) • DDX41 (DEAD-Box Helicase 41) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2) • BCORL1 (BCL6 Corepressor Like 1)

TP53 mutation • TET2 mutation • U2AF1 mutation • Chr del(5q) • Chr del(7q) • TET2 deletion

2years

Somatic TET2 Mutations Prime the Immune System for Response to Immune Checkpoint Blockade (ASH 2023)

To explore whether TET2-CH might identify patients primed for ICB response, we screened for CH in the prospectively collected baseline PBMCs from 90 solid tumour patients treated in a Phase 2 trial of the PD-1 inhibitor Pembrolizumab (NCT02644369)...Mechanistically, this occurs through lineage-specific promoter hypermethylation and gene silencing. Further study of TET2-CH as a potential biomarker of ICB response is warranted and targeting TET2-regulated pathways may yield novel strategies to improve immunotherapy outcomes.

2 years ago

Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker • Checkpoint block

CD8 (cluster of differentiation 8) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C)

TET2 mutation • TET2 deletion

Keytruda (pembrolizumab)

over2years

Tet2-mutant Clonal Hematopoiesis Drives Resistance to MAPK Inhibitors in BRAFV600E-mutant Anaplastic Thyroid Cancer (ATA 2023)

We performed competitive bone marrow transplants (bmt) from tamoxifen‐treated C57BL/6J CD45... CH‐mutations lead to resistance to dab/tram in murine ATC. Our work opens new avenues for the selective targeting of tumor‐promoting inflammation in ATC.

over 2 years ago

TP53 (Tumor protein P53) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CCL2 (Chemokine (C-C motif) ligand 2)

BRAF V600E • BRAF V600 • TET2 mutation • TET2 deletion

MSK-IMPACT

tamoxifen

over2years

TET2-mutations reshape tumour infiltrating leukocytes to promote immunotherapy response (EACR 2023)

MC-38 colon adenocarcinoma cells were subcutaneously implanted and mice were treated with anti-PD-1 or control antibodies +/- cell depleting antibodies or clodronate...Tet2-het TILs exhibited hypermethylation of genetic pathways regulating leukocyte differentiation.ConclusionTET2-CH is associated with increased odds of 6 month clinical benefit in immunotherapy-treated melanoma patients. In a mouse TET2-CH model, Tet2-loss of function reshapes the TIL epigenome and enhances effector/memory fate while relieving exhaustion and inhibiting regulatory T cell fate, to drive immunotherapy response.

over 2 years ago

PD(L)-1 Biomarker • IO biomarker • Tumor-infiltrating-leukocyte

CD8 (cluster of differentiation 8) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD4 (CD4 Molecule)

TET2 mutation • TET2 deletion