The study investigates the impact of TET2 mutations on the hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in myeloid cancers. TET2, an enzyme that converts 5-mC to 5-hmC, is frequently mutated in myeloid malignancies, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML). The research shows that TET2 mutations associated with these cancers reduce its catalytic activity, leading to uniformly low levels of 5-hmC in genomic DNA from patient samples compared to healthy controls. In mouse models, depletion of *Tet2* in hematopoietic precursors promotes differentiation towards monocyte/macrophage lineages. While there is no significant difference in DNA methylation between high and low 5-hmC levels in patient samples, low 5-hmC levels are associated with hypomethylation at most differentially methylated CpG sites. The findings suggest that TET2 plays a crucial role in normal myelopoiesis and that disruption of its enzymatic activity may contribute to myeloid tumorigenesis. Measuring 5-hmC levels in myeloid malignancies could serve as a valuable diagnostic and prognostic tool, potentially aiding in the development of targeted therapies.The study investigates the impact of TET2 mutations on the hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in myeloid cancers. TET2, an enzyme that converts 5-mC to 5-hmC, is frequently mutated in myeloid malignancies, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemias (AML). The research shows that TET2 mutations associated with these cancers reduce its catalytic activity, leading to uniformly low levels of 5-hmC in genomic DNA from patient samples compared to healthy controls. In mouse models, depletion of *Tet2* in hematopoietic precursors promotes differentiation towards monocyte/macrophage lineages. While there is no significant difference in DNA methylation between high and low 5-hmC levels in patient samples, low 5-hmC levels are associated with hypomethylation at most differentially methylated CpG sites. The findings suggest that TET2 plays a crucial role in normal myelopoiesis and that disruption of its enzymatic activity may contribute to myeloid tumorigenesis. Measuring 5-hmC levels in myeloid malignancies could serve as a valuable diagnostic and prognostic tool, potentially aiding in the development of targeted therapies.