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Author Notes:

Correspondence: jaenisch@wi.mit.edu (R.J.), peng.jin@emory.edu (P.J.), mxx51@miami.edu (M.X.)

Z.Z., L.C., and M.M.D. are co-first authors.

Z.Z., M.M.D., F.P., J.W., and S.C. performed the experiments involving animal models; Z.Z., Y.Z., Z.C., H.S., and W.Y. performed experiments involving human specimens; H.N. reviewed the blood smears and histopathologic sections; L.C., L.L., Z.Q., and P.J. analyzed the RNA-seq/5mC/5hmC data.

M.M.D., O.W., S.D.N., F.-C.Y., and R.J. participated in designing the study and revised the manuscript; P.J. and M.X. designed and supervised the studies, performed the experiments, analyzed data, wrote the manuscript, and are responsible for its final draft.

Accession Numbers: Sequence data have been deposited to the NCBI GEO and are available under accession number GEO: GSE73611.

Subjects:

Research 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.).

M.M.D. is a Damon Runyon Postdoctoral Fellow.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • HEMATOPOIETIC STEM-CELLS
  • MAMMALIAN DNA
  • SELF-RENEWAL
  • IN-VIVO
  • 5-HYDROXYMETHYLCYTOSINE
  • LEUKEMIA
  • LEADS
  • DIFFERENTIATION
  • METHYLATION
  • MOUSE

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

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Journal Title:

Cell Reports

Volume:

Volume 13, Number 8

Publisher:

, Pages 1692-1704

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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