The expansive reach of TET2

Abstract

TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms (MPN). Here we show that the level of 5-hmC is decreased in granulocyte DNA from MPN patients with TET2 mutations, compared to granulocyte DNA from healthy individuals. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34(+) cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34(+) cells skews progenitor differentiation toward the granulo-monocytic lineage at the expense of lymphoid and erythroid lineages. In addition by monitoring in vitro granulo-monocytic development we find a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates to the pathogenesis of myeloid malignancies through disturbing myeloid differentiation.