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<div>Abstract<p>The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten–eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type–specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model <i>TET2</i> loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and <i>in vivo</i> competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of <i>TET2</i>-mutant clones <i>in vivo</i>. These results demonstrate the key role of 5hmC in normal hematopoiesis and <i>TET2-</i>mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis.</p>Significance:<p>We show that 5-hydroxymethylation profiles are cell type–specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. <i>TET2</i> loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of <i>TET2</i> KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes.</p><p><i><a href="" target="_blank">This article is highlighted in the In This Issue feature, p. 265</a></i></p></div>

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