Human TET2

duration

Cross-sectional

experimental_model

Five myeloproliferative-disorder patient samples with clonal analysis of progenitors

exposure

No intervention; clonal ordering within patient samples

limitations

Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease.

organism

Homo sapiens

plain_language

Where both were present, the TET2 damage came first.

primary_references

[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069

tissue

Haematopoietic stem and progenitor cells

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 23–31

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Five myeloproliferative-disorder patient samples with clonal analysis of progenitors · source_derived_draft · unverified_draft

## tet2-defect-precedes-jak2-v617f TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders. Model/species: Five myeloproliferative-disorder patient samples with clonal analysis of progenitors Organism: Homo sapiens Tissue/system: Haematopoietic stem and progenitor cells Exposure: No intervention; clonal ordering within patient samples Duration: Cross-sectional Limits: Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069

duration

Cross-sectional

experimental_model

320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses

exposure

No intervention; observational sequencing of patient material

limitations

A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone.

organism

Homo sapiens

plain_language

About one in seven patients with these blood cancers carried a damaged copy of TET2.

primary_references

[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069

tissue

Haematopoietic cells and bone marrow

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 13–21

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses · source_derived_draft · unverified_draft

## tet2-mutated-across-myeloid-neoplasms Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9). Model/species: 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses Organism: Homo sapiens Tissue/system: Haematopoietic cells and bone marrow Exposure: No intervention; observational sequencing of patient material Duration: Cross-sectional Limits: A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069

duration

Cross-sectional

experimental_model

Human lymphoid disorder samples with progenitor colony assays

exposure

No intervention; observational sequencing

limitations

Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour.

organism

Homo sapiens

plain_language

The same damaged gene also turns up in lymphoid cancers, not only myeloid ones.

primary_references

[quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003

tissue

Lymphoid tumour cells and immature progenitors

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 83–91

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human lymphoid disorder samples with progenitor colony assays · source_derived_draft · unverified_draft

## tet2-mutation-in-lymphoid-disorders TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential. Model/species: Human lymphoid disorder samples with progenitor colony assays Organism: Homo sapiens Tissue/system: Lymphoid tumour cells and immature progenitors Exposure: No intervention; observational sequencing Duration: Cross-sectional Limits: Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour. Primary reference: [quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003

availability_state

machinery_impairment Imported condition classification; unverified.

duration

Cross-sectional

experimental_model

Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein

exposure

No intervention; naturally occurring mutations

limitations

Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain.

organism

Homo sapiens

plain_language

Patients with a damaged TET2 had less of the chemical mark the enzyme makes.

primary_references

[ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586

tissue

Bone marrow genomic DNA

trigger_kind

machinery_impairment Imported condition classification; unverified.

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 33–41

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein · source_derived_draft · unverified_draft

## tet2-mutation-lowers-marrow-5hmc Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study. Model/species: Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein Organism: Homo sapiens Tissue/system: Bone marrow genomic DNA Exposure: No intervention; naturally occurring mutations Duration: Cross-sectional Limits: Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain. Primary reference: [ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586

availability_state

machinery_impairment Imported condition classification; unverified.

duration

Culture experiments

experimental_model

Human HAP1 cells with single and double TET knockouts

exposure

Vitamin C treatment of wild-type and TET-knockout cells

limitations

A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation.

organism

Homo sapiens

plain_language

Vitamin C cannot fully substitute for a TET2 that is missing.

primary_references

[kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1

tissue

HAP1 cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 183–191

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human HAP1 cells with single and double TET knockouts · source_derived_draft · unverified_draft

## vitamin-c-cannot-replace-lost-tet2 TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones. Model/species: Human HAP1 cells with single and double TET knockouts Organism: Homo sapiens Tissue/system: HAP1 cell line Exposure: Vitamin C treatment of wild-type and TET-knockout cells Duration: Culture experiments Limits: A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation. Primary reference: [kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1

availability_state

machinery_impairment Imported condition classification; unverified.

duration

Culture experiments

experimental_model

TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation

exposure

Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases

limitations

Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit.

organism

Homo sapiens

plain_language

Whether vitamin C can revive the enzyme depends on which mutation the patient has.

primary_references

[mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9

tissue

Myeloid neoplasia cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 173–181

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation · source_derived_draft · unverified_draft

## ascorbate-restoration-depends-on-mutation-and-acetylation The ability of ascorbic acid to restore TET2 activity in cells depended on N-terminal and C-terminal lysine acetylation and on the nature of the TET2 mutation. Model/species: TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation Organism: Homo sapiens Tissue/system: Myeloid neoplasia cells Exposure: Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases Duration: Culture experiments Limits: Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit. Primary reference: [mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9

duration

Culture treatment

experimental_model

Myeloid leukaemia cell lines and primary human AML models

exposure

All-trans retinoic acid

limitations

A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A.

organism

Homo sapiens

plain_language

Retinoic acid made leukaemia cells produce more of the TET2 enzyme.

primary_references

[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379

tissue

Myeloid leukaemia cells

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 143–151

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Myeloid leukaemia cell lines and primary human AML models · source_derived_draft · unverified_draft

## atra-induces-tet2-transcription All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells. Model/species: Myeloid leukaemia cell lines and primary human AML models Organism: Homo sapiens Tissue/system: Myeloid leukaemia cells Exposure: All-trans retinoic acid Duration: Culture treatment Limits: A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379

duration

In vivo to survival

experimental_condition

Untreated or single-agent primary human AML models All-trans retinoic acid administered · All-trans-retinoic acid Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_condition

Untreated or single-agent primary human AML models Ascorbate administered · L-Ascorbate Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_contrast

{"intervention": "All-trans retinoic acid plus ascorbate", "comparator": "Untreated or single-agent primary human AML models", "endpoint": "Leukaemia stem cell self-renewal and survival", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "all-trans-retinoic-acid", "state": "All-trans retinoic acid administered"}, {"entity_slug": "ascorbate", "state": "Ascorbate administered"}]} Explicit extracted experimental comparison; source-derived draft.

experimental_model

Tet1/2/3-deficient mice and primary human AML models

exposure

All-trans retinoic acid combined with ascorbate

limitations

A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone.

organism

Mus musculus and Homo sapiens

plain_language

Retinoic acid and vitamin C together worked better than either was expected to alone.

primary_references

[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379

tissue

Leukaemia stem cells

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 153–161

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet1/2/3-deficient mice and primary human AML models · source_derived_draft · unverified_draft

## atra-with-ascorbate-reduces-lsc-self-renewal All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival. Model/species: Tet1/2/3-deficient mice and primary human AML models Organism: Mus musculus and Homo sapiens Tissue/system: Leukaemia stem cells Exposure: All-trans retinoic acid combined with ascorbate Duration: In vivo to survival Limits: A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379

duration

Culture experiments

experimental_model

AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis

exposure

Vitamin C, with and without SLC2A3 knockdown

limitations

Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome.

organism

Homo sapiens

plain_language

If the cell cannot take vitamin C in, the vitamin cannot restore the enzyme.

primary_references

[liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8

tissue

Leukaemic blasts

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 163–171

Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis · source_derived_draft · unverified_draft

## slc2a3-gates-vitamin-c-tet2-restoration In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C. Model/species: AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis Organism: Homo sapiens Tissue/system: Leukaemic blasts Exposure: Vitamin C, with and without SLC2A3 knockdown Duration: Culture experiments Limits: Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome. Primary reference: [liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8