biostudies-literatureYuita HHHS | National Institutes of HealthMEXT | Japan Society for the Promotion of ScienceNCRR NIH HHSUniversity of California Institute for Mexico and the United StatesJapan Agency for Medical Research and DevelopmentMinistry of Education, Culture, Sports, Science and TechnologyNCI NIH HHSNational Research Foundation of KoreaNIH HHSUlsan National Institute of Science and Technologye2214824120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9963276biostudies-literatureUnknown120(6)The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three <i>Tet</i> genes in the mouse genome. <i>Tet1/2/3-inducible TKO</i> (<i>iTKO</i>) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of <i>Tet iTKO</i> bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the <i>stefin/cystatin</i> gene cluster on mouse chromosome 16. In patients with AML, high <i>stefin/cystatin</i> gene expression correlates with poor clinical outcomes. IncreasedProceedings of the National Academy of Sciences of the United States of AmericaInducible disruption of <i>Tet</i> genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.PMC99632762018R1A6A1A03025810JP20gm1210003S10OD016262JP19H056501.180075.011.220023.01(A) 20KK0351R35 CA2100432019R1F1A1063340UC MEXUS-CONACYT FellowshipS10 OD016262S10 RR027366S10RR027366Rao AKo MJeong HCheng AXNakayama TAn JLopez-Moyado IFYuita HOnodera AScott-Browne JfalseInducible disruption of <i>Tet</i> genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three <i>Tet</i> genes in the mouse genome. <i>Tet1/2/3-inducible TKO</i> (<i>iTKO</i>) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of <i>Tet iTKO</i> bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the <i>stefin/cystatin</i> gene cluster on mouse chromosome 16. In patients with AML, high <i>stefin/cystatin</i> gene expression correlates with poor clinical outcomes. Increased2023-01-01T00:00:00Z2023 Feb2026-03-18T14:08:16.315Z2025-04-04T20:04:50.913ZS-EPMC99632763740630310.1073/pnas.2214824120