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

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posted on 13.06.2016, 00:00 by Z Zhao, L Chen, MM Dawlaty, F Pan, O Weeks, Y Zhou, Z Cao, H Shi, J Wang, L Lin, S Chen, W Yuan, Z Qin, H Ni, SD Nimer, FC Yang, R Jaenisch, P Yin, M Xu
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 5 hmC and 5 mC 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.

Funding

This work was supported by grants from the NIH (HL112294 to M.X., CA172408 to M.X. and F.-C.Y., NS079625 and MH102690 to P.J., HDO45022 and CA084198 to R.J.), Simons Foundation (to R.J. and P.J.), and National Nature Science Foundation of China (#81328003 to W.Y.).

History

Publisher Statement

This is a copy of an article published in Elsevier (Cell Press). © Zhao et al., 2015, Cell Reports 13, 1692–1704 November 24, 2015. © 2015 The Authors. http://dx.doi.org/10.1016/j.celrep.2015.10.037

Publisher

Elsevier (Cell Press)

Language

en_US

issn

2211-1247

Issue date

24/11/2015

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