Table 1 Phenotypes of Tet1, Tet2, and Tet3 knockout mice and compound-knockout mice
From: Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis
Mouse lines | HSCs and MPPs | Latency | Hematopoietic diseases |
|---|---|---|---|
Tet1−/− mice [44] | Higher frequencies of immature B cells Increased self-renewal capacity and frequency of B-cell progenitors | 18–24 months | B-cell lymphoma |
Expansion of LSK HSPCs and GMPs. Increased CHRC in competitive transplantation Dramatically increased proportions of Gr1+/Mac1+ cells in their BM, spleens, and PB after 1 year Genome-wide increase in DNA methylation of active enhancers and downregulation of genes including Gata2 | 12–20 months | Develop microbial-induced MDS/MPNs and CMML in > 90% of the animals at 12–15 months Approximately 4–10% of animals develop B-cell malignancies or T-cell malignancies | |
Tet3−/− mice | Die at birth | ||
Vav1CreTet3fx/fx mice | A minor increase in the frequency of LSK HSPCs and a decrease in the frequency and absolute numbers of HSCs in BM | Healthy | |
Vav1CreTet2fx/fx mice Mx1CreTet2fx/fx mice | Dramatically increased proportions of Gr1+/Mac1+ cells in BM, spleen, and PB | 12–14 months | CMML like |
Tet2KD mice [56] (H1367Y/D1369A) | Slightly increased LSK HSPCs, significant expansion of, CMPs and GMPs Distinct gene expression pattern compared to Tet2−/− | Starting at 4 months 12–20 months | Predominantly MDS/CMML |
LysMCreTet2fx/fx mice [48] | Healthy | ||
Tet2gt mice (gene trap at the 2ndintron) causes an 80% decrease in Tet2 mRNA levels and a 50% decrease in 5hmC levels [57]. | Cooperate with TCR signaling to decrease FoxO1 expression and activity | ∼17 months | Lymphoproliferation of Tfh-like cells |
VavCreTet2fl/fl OT-II T-cell receptor transgene [58] | 10 months | Developed AITL-like lymphomas | |
CD4CreTet2fx/fx[59] | Minimal effect on thymic T-cell development | Increased CD8+ memory T-cells after viral infection, improved protection upon subsequent re-infection | |
Germinal center (GC) hyperplasia impairs plasma cell differentiation and promotes B-cell lymphomagenesis Increase in AID-mediated mutations GC B-cell hyperplasia and impaired plasma cell differentiation Decreased expression of Prdm1 | 16 months | CLL-like Precipitated malignancy induced by T-cell leukemia/lymphoma 1A (TCL1A) Δexon 3 | |
CD19CreTet2fx/fxTet3fx/fx [63] | Hyperactivation of B- and T-cells, autoantibody production Downregulation of CD86 | Lupus-like disease | |
Block at the transition from the pro–B-cell to the pre–B-cell stage Down-regulation of IRF4 Increased CpG methylation at the Igκ 3' and distal enhancers, influencing chromatin accessibility of B-cell-specific TFs such as E2A or PU.1 | 5–6 months | Developed B-cell lymphomas with splenomegaly and lymphadenopathy. Resemble human B-ALL | |
Mx1CreTet2fx/fxTet3fx/fx [20] Mx1CreTet2fx/+Tet3fx/fx [65] Mx1CreTet2fx/fxTet3fx/+ | Uncontrolled expansion of CD11b+Gr1+ immature monocyte/granulocytes Tet2 and Tet3 are dose-dependent | 1–3 months 5–10 months | AML |
Tet1−/−Tet2−/− mice [41] | Increases CLP/BLP compartment and affects B-cell development HSCs exhibit an increased short-term, but not long-term, hematopoietic repopulating capacity Express genes of human B-cell malignancies such as Lmo2 genes of Bcl6, Myc, Pten, and Blk | 15–20 months | B -ALL |
Tet2−/−CD4CreTet3fx/fx [17] | iNKT cells skew toward the NKT17 lineage, stimulated by TCR signaling | 2 months | Aggressive PTCL-like syndrome originating from iNKT cells. CD1d-restricted iNKT cell lymphoma |
Foxp3CreTet2 fx/fxTet3 fx/fx [66] | Hypermethylation at FoxP3 promoter and intronic enhancer CNS2, impaired Treg cell differentiation and function | 1 month? | Develop autoimmune disease Develop inflammatory disease |
Tet1−/−Cd4CreTet2 fx/fx [67] Tet1−/−Foxp3CreTet2 fx/fx | H2S regulates Tet1 and Tet2 expression via sulfhydration of NFYB CD4+ cells show strong skewing towards Tfh/Th17 phenotypes Hypermethylation at FoxP3 promoter and intronic enhancer CNS2, impaired Treg cell differentiation and function | Develop autoimmune disease |