Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors

Abstract

TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid ma-lignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. 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 lym-phoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found 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 in the pathogenesis of my-eloid malignancies through the disturbance of myeloid differentiation. (Blood. 2011;118(9):2551-2555)

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…+ monocytic lineage in ex vivo culture experiment [60]. Indeed, Aid-deficient mice as well as AID-silenced human BM CD34 + cells also demonstrated myeloid skewing, suggesting that TET2/AID active DNA demethylation pathway might play an essential role in myeloid fate commitment [43].…”

5-hydroxymethylcytosine

“…If the conversion of 5-mC to 5-hmC was inhibited due to mutation of TET2 gene, it might disturb the differentiation of human hematopoietic progenitors. 35,56 TET2 disruption affects 5-hmC levels in human myeloid cells and may participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation, which may explain the reason why TET2 gene expression decreases during the progression of chronic myeloid leukemia (CML). Therefore TET2 mutation or loss of function is closely related to 5-mC and 5-hmC in patients with CMML and CML.…”

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

“…[23][24][25] As one of the most frequent mutations found in myeloid malignancies, TET2 has been proposed to be a tumor suppressor as loss of function tends to lead to disruption of progenitor myeloid differentiation leading to disease progression. 81 Its function is to convert 5-methlycytosine to 5-hdroxymethyl cytosine (5-hmc) and it is, therefore, involved in the epigenetic s. Beurlet et al 12 haematologica | 2013; 98(1) Figure 2. Altered stem cell and niche in MDS mouse models…”