Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

Zhigang Zhao, Li Chen, Meelad M. Dawlaty, Feng Pan, Ophelia Weeks, Yuan Zhou, Zeng Cao, Hui Shi, Jiapeng Wang, Li Lin, Shi Chen, Weiping Yuan, Zhaohui Qin, Hongyu Ni, Stephen D. Nimer, Feng Chun Yang, Rudolf Jaenisch, Peng Jin, Mingjiang Xu

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs show overlapping and unique 5hmC and 5mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloid malignancies in comparison to Tet2-/- mice and in contrast develop lethal B cell malignancies. Transcriptome analysis of DKO tumors reveals expression changes in many genes dysregulated in human B cell malignancies, including LMO2, BCL6, and MYC. These results highlight the critical roles of TET1/2 individually and together in the pathogenesis of hematological malignancies.

Original languageEnglish (US)
Pages (from-to)1692-1704
Number of pages13
JournalCell Reports
Volume13
Issue number8
DOIs
StatePublished - Nov 24 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhao, Z., Chen, L., Dawlaty, M. M., Pan, F., Weeks, O., Zhou, Y., Cao, Z., Shi, H., Wang, J., Lin, L., Chen, S., Yuan, W., Qin, Z., Ni, H., Nimer, S. D., Yang, F. C., Jaenisch, R., Jin, P., & Xu, M. (2015). Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. Cell Reports, 13(8), 1692-1704. https://doi.org/10.1016/j.celrep.2015.10.037