Table 2 Collaboration of other leukemic oncogenes with Tet2^MT in malignant hematopoietic development in mouse models

Vav^creTet2^fx/fxJak2^V617F mice [132]

TET2^trap/+Jak2^V617F mice [133]

Enhanced competitive advantage to Jak2^V617F-mutant HSCs

TET2 loss prevents the exhaustion of JAK2^V617F HSCs

Sustain MPNs over long periods of time

1–6 months

Accelerated MPNs

Cre^ERTEzh2^fx/fxTet2^trap/trap mice [134]

Enhanced repopulating capacity of HSCs and extramedullary hematopoiesis

10 months

Enhanced pathogenesis of MDS/MPN, MDS

Mx1-cre Asxl1^fx/fxTet2^fx/fx mice [135]

Tet2 deletion restores self-renewal of Asxl1-deficient HSCs

6–7 months

Developed MDS phenotype with hastened death

Mcpt5^CreTet2^fx/fxKit^D816V  [136, 137]

Tet2 deletion increases proliferation and impairs differentiation of BM mast cells

Tet2 deletion in BM mast cells induces c-MYC upregulation via PI3K activation. Block in the differentiation of KIT D814V positive BMMCs

9 months

More aggressive forms of mastocytosis

Vav^creTet2^fx/fxFlt3^ITD mice [138]

Tet2^−/−Flt3^ITD mice [139]

Flt3^ITD and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus

Expansion of myeloid cell compartment, and defects in maturation

Alters the BM microenvironment and produces more pro-inflammatory cytokines including IL-5, IL-6, CXCL5, MIP-1A, MIP-1B, MIP-2, TNFα, IL-13, and IL-15

9–12 months

5 months

Develop AML refractory to standard AML chemotherapy and FLT3-targeted therapy

AML

AML1-ETO/Cre^ERTTet2^fx/fx, an infection and transplantation model [18].

Hypermethylation of enhancer elements results in lowered gene expression

6 months

Greatly accelerated onset of AML

DNMT3A^R882HTet2^−/− mice, an infection and transplantation model [140]

Accumulation of mutant HSPCs with impaired differentiation capability

within

6 months

AITL-like, AML-like, and T-ALL-like diseases in first transplantation recipients and a majority of AITL-like diseases in secondary recipients

Mx1^creDnmt3a^fx/fxTet2^−/− mice [141]

Marked increases in LSK HSPCs

Synergistic dysregulation of HSC- and RBC-associated genes

Klf1 and Epor erythroid genes promote mutant HSPC self-renewal

5 months

BM transplantation recipient mice die of multiple hematologic abnormalities

1. ~ 10% BM failure

2.50% T-cell thymic lymphoma

3.B220⁺CD19⁻ salivary gland infiltration, mature B-cell lymphoma in primary mice and develop B-ALL in recipients

Vav^creNcstn^fx/fxTet2^fx/fx [142]

Enlargement of the GMP compartment due to differentiation defects

6 months

Die of AML-like diseases

Mx1^CreTet2^fx/fxNras^G12D mice [143, 144]

Expansion of HSCs and MPPs. Increased response to cytokine stimulation. Enhanced HSC competitiveness and self-renewal

9–12 months

Accelerated, transplantable CMML disease

AML [143]

Vav-^iCre+Pu.1^URΕ∆/+Tet2^fx/fx

Vav-^iCre+Pu.1^URΕ∆/+Tet2^fx/+

(with 30% reduction of Pu.1) [72]

Age-related reduction of Pu.1 expression. Increased methylation in Pu.1 binding motifs

10–20 months

Develop AML during aging with median survival 623 and 290 days respectively

IDH2^R140QFlt3^ITD mice [145]

IDH2^R140Q−t induces a block of erythroid differentiation in KSL cells

7 months

AML with T-cell markers

Hmga2 expression in Tet2^−/− mice [146]

Hmga promotes Igf2bp2 expression and impairs differentiation of Tet2^−/− myeloid cells

Progressive MDS and AML

ERT^CreTet2^fx/fxBcor^ΔE9−10/y mice [147]

3–6 months

Progressive MDS

Mx1-Cre Sf3b^1K700E/+ Tet2^−/− mice [148]

12 weeks

Earlier onset and more severe MDS

T-cells

Vav^creIdh2^R172K mice [149]

Slight increase in 2-HG levels in ICOS⁺ T_fh cells

Only studied for 3–7 month olds

Impairs lymphocyte development. CD4⁺ and CD8⁺ naive T-cells were decreased, while CD8⁺ central memory cells were increased

CD4-RhoA^G17V TG mice [58]

Relatively increased TFH-cell populations are accompanied by markedly reduced naive T-cells

Autoimmunity due to CD4⁺ Th17 cell infiltration

RhoA^G17V transduction of Tet2^−/− T cells [150]

Increased Ki67⁺CD4⁺ T-cells, CD4⁺CD44⁺ T-cells and CD4⁺CXCR5⁺Bcl-6⁺Tfh

Reduction in Treg and FAS⁺GL-7⁺ GC B- cells

Partial AITL gene signature

Increased cytokine production, such as IL-6 and INFγ

5 months

Inflammatory diseases or aggressive cancer (PTCL-Tfh) developed

Cd4^CreERT2Tet2^fx/fxRhoa^G17V mice [151]

Tfh (CD4⁺CXCR5⁺PD1⁺, ICOS⁺, Bcl-6⁺)

Tfh gene signature

AITL gene signature

6 months

Aggressive AITL-like lymphomas

Vav^CreTet2^fx/fxCd4-Rhoa^G17V (transgene) [58]

Vav^CreTet2^fx/fxCd4-Rhoa^G17V OT-II mice

Tfh (CD4⁺CXCR5⁺PD1⁺Bcl-6⁺)

7 months

PTCL and developed autoimmune syndromes with Tfh cell expansion and autoantibody generation

Mice bearing an OT-II T-cell receptor transgene developed AITL-like lymphomas