Transcriptional control and signal transduction, cell cycle

DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

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Abstract

TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3AR882H) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3AR882H Tet2−/− progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3AR882H Tet2−/− T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3AR882H Tet2−/− T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3AR882H Tet2−/− progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.

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Acknowledgements

We thank members of the Bernard laboratory for helpful discussions, Julie Mouillaux for her involvement in this project, Patrick Gonin from the Gustave Roussy animal facility for excellent mouse care as well as Yann Lecluse and Philippe Rameau from the Gustave Roussy Flow Cytometry Core Facility. We also thank the Gustave Roussy Genomic Platform for high-throughput sequencing. Work in the laboratory was supported by grants from INSERM, Institut National du Cancer (INCA), 2013-1-PL BIO-09, INCa-DGOS-INSERM 6043, Ligue Nationale Contre le Cancer (LNCC), Fondation pour la Recherche Médicale (FRM) and Association Laurette Fugain. The work in the laboratory of KH was supported by the Danish Cancer Society, the European Research Council (294666_DNAMET), the Danish National Research Foundation (DNRF82) and the Novo Nordisk Foundation. LS is supported by fellowships from Cancéropôle Ile de France and Fondation Association pour la recherche sur le Cancer (ARC).

Author contributions

LS drafted the manuscript. LS and LC designed, performed and analyzed results. VDV, ElM, JC, EnM, CkL NM, ND, PG, MW, FP, MP, AB and KH performed experiments and analyzed data. MBD, PhD, MF, SG and PaD analyzed results. TM designed experiments, analyzed results and drafted the manuscript. OAB designed the project, experiments and wrote the manuscript.

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Correspondence to O A Bernard.

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Scourzic, L., Couronné, L., Pedersen, M. et al. DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice. Leukemia 30, 1388–1398 (2016) doi:10.1038/leu.2016.29

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