TET2 Loss Dysregulates the Behavior of Bone Marrow Mesenchymal Stromal Cells and Accelerates Tet2−/−-Driven Myeloid Malignancy Progression

Rong Li, Yuan Zhou, Zeng Cao, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Shi Chen, Jie Bai, Weiping Yuan, Tao Cheng, Mingjiang Xu, Feng-Chun Yang, Zhigang Zhao

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation. In addition, Tet2 loss alters BMSCs in promoting Tet2-deficiency-mediated myeloid malignancy progression. Tet2 loss in BMSCs also dysregulates hydroxylation of 5-methylcytosine (5mC) and the expression of genes that are key for BMSC proliferation and osteoblast differentiation, leading to alteration of biological characteristics in vivo. These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation and provide evidence that dysregulation of epigenetic modifiers in BMSCs contributes to the progression of myeloid malignancies. In this article, Zhao and colleagues demonstrated that TET2 plays an important role in regulating the behavior of BMSCs in addition to its intrinsic role in HSPCs to participate in aberrant hematopoiesis. Moreover, they also show that BMSCs are the most important niche cell components in Tet2−/− mice that contribute to the progression of Tet2-deletion-driven myeloid malignancies.

Keywords

  • bone marrow mesenchymal stromal cells
  • bone marrow niche
  • myeloid malignancies
  • TET2

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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