This study investigates the role of TET2 in myeloid cancers, showing that mutations in TET2 impair its catalytic activity, leading to reduced 5-hydroxymethylcytosine (5-hmC) levels and increased DNA hypomethylation. TET2 is a key enzyme that converts 5-methylcytosine (5-mC) to 5-hmC in DNA. Mutations in TET2 are frequently found in myeloid malignancies such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML). These mutations disrupt TET2 function, leading to impaired myelopoiesis and promoting myeloid tumorigenesis. Bone marrow samples from patients with TET2 mutations showed uniformly low levels of 5-hmC compared to healthy controls. In experiments, depletion of Tet2 in mouse hematopoietic precursors skewed differentiation towards monocyte/macrophage lineages. Patients with low 5-hmC levels showed hypomethylation at most differentially methylated CpG sites. These findings suggest that TET2 is essential for normal myelopoiesis and that its dysfunction favors myeloid tumorigenesis. The study also identified specific mutations in TET2 that affect its catalytic activity, such as H1881 and R1896, which are predicted to bind Fe²+ and 2OG, respectively. These mutations were found in patients with myeloid malignancies. The study further demonstrated that TET2 mutations are strongly associated with low 5-hmC levels in patients with myeloid malignancies. Analysis of DNA methylation status showed that TET2 mutations are correlated with hypomethylation at CpG sites. The study also examined the expression of TET2 in hematopoietic cell subsets and found that TET2 is highly expressed in multipotent progenitors and myeloid progenitors, but low in mature granulocytes and high in monocytes. TET2 depletion promoted the expansion of monocyte/macrophage cells in the presence of certain cytokines, indicating its role in normal myelopoiesis. The study further showed that 5-hmC levels in tumor samples correlated with DNA methylation status. Tumor samples with low 5-hmC levels showed hypomethylation at CpG sites, suggesting that TET2 loss-of-function is predominantly associated with decreased methylation at CpG sites. The study concludes that TET2 mutations are strongly correlated with myeloid malignancies and that 5-hmC levels may serve as a diagnostic and prognostic tool for these cancers. The findings highlight the importance of TET2 in maintaining normal DNA methylation patterns and suggest that targeting TET2 or 5-hmThis study investigates the role of TET2 in myeloid cancers, showing that mutations in TET2 impair its catalytic activity, leading to reduced 5-hydroxymethylcytosine (5-hmC) levels and increased DNA hypomethylation. TET2 is a key enzyme that converts 5-methylcytosine (5-mC) to 5-hmC in DNA. Mutations in TET2 are frequently found in myeloid malignancies such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML). These mutations disrupt TET2 function, leading to impaired myelopoiesis and promoting myeloid tumorigenesis. Bone marrow samples from patients with TET2 mutations showed uniformly low levels of 5-hmC compared to healthy controls. In experiments, depletion of Tet2 in mouse hematopoietic precursors skewed differentiation towards monocyte/macrophage lineages. Patients with low 5-hmC levels showed hypomethylation at most differentially methylated CpG sites. These findings suggest that TET2 is essential for normal myelopoiesis and that its dysfunction favors myeloid tumorigenesis. The study also identified specific mutations in TET2 that affect its catalytic activity, such as H1881 and R1896, which are predicted to bind Fe²+ and 2OG, respectively. These mutations were found in patients with myeloid malignancies. The study further demonstrated that TET2 mutations are strongly associated with low 5-hmC levels in patients with myeloid malignancies. Analysis of DNA methylation status showed that TET2 mutations are correlated with hypomethylation at CpG sites. The study also examined the expression of TET2 in hematopoietic cell subsets and found that TET2 is highly expressed in multipotent progenitors and myeloid progenitors, but low in mature granulocytes and high in monocytes. TET2 depletion promoted the expansion of monocyte/macrophage cells in the presence of certain cytokines, indicating its role in normal myelopoiesis. The study further showed that 5-hmC levels in tumor samples correlated with DNA methylation status. Tumor samples with low 5-hmC levels showed hypomethylation at CpG sites, suggesting that TET2 loss-of-function is predominantly associated with decreased methylation at CpG sites. The study concludes that TET2 mutations are strongly correlated with myeloid malignancies and that 5-hmC levels may serve as a diagnostic and prognostic tool for these cancers. The findings highlight the importance of TET2 in maintaining normal DNA methylation patterns and suggest that targeting TET2 or 5-hm