Article open access publication

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

Leukemia, Springer Nature, ISSN 1476-5551

Volume 30, 6, 2016

DOI:10.1038/leu.2016.29, Dimensions: pub.1006647138, PMC: PMC4869893, PMID: 26876596,

Authors

Scourzic, L (1) (2) (3) (4)
Couronné, L (1) (2) (3) (4)
Pedersen, M T (5) (6)
Della Valle, V (1) (2) (3) (4)
Diop, M (1) (2) (3) (4)
Mylonas, E (1) (2) (3) (4)
Calvo, J (1) (2) (7) (8)
Mouly, E (1) (2) (3) (4)
Lopez, C K (2) (3) (4)
Martin, N (9) (10)
Fontenay, M (11) (12)
Bender, A (13)
Guibert, S (13)
Dubreuil, P (14) (15)
Dessen, P (1) (2) (3) (4)
Droin, N (1) (2) (3) (4)
Pflumio, F (1) (2) (7) (8)
Weber, M (13)
Gaulard, P (9) (10) (16)
Helin, K (5) (6)
Mercher, T (2) (3) (4)
Bernard, O A * (1) (2) (3) (4)

* Corresponding author

Affiliations

Organisations

  1. (1) Ligue Nationale Contre le Cancer, grid.452770.3
  2. (2) University of Paris-Sud, grid.5842.b
  3. (3) INSERM U1170, Villejuif, France
  4. (4) Institut Gustave Roussy, grid.14925.3b
  5. (5) Centre for Epigenetics, Copenhagen, Denmark
  6. (6) University of Copenhagen, grid.5254.6, KU
  7. (7) CEA Fontenay-Aux-Roses, grid.457349.8
  8. (8) INSERM U967, Fontenay-aux-Roses, France
  9. (9) Mondor Institute of Biomedical Research, grid.462410.5
  10. (10) Paris 12 Val de Marne University, grid.410511.0
  11. (11) Hôpital Cochin, grid.411784.f
  12. (12) Institut Cochin, grid.462098.1
  13. (13) University of Strasbourg, grid.11843.3f
  14. (14) Centre de Recherche en Cancérologie de Marseille, grid.463833.9
  15. (15) Institute Paoli-Calmettes, grid.418443.e
  16. (16) Hôpitaux Universitaires Henri Mondor, grid.412116.1

Countries

France

Denmark

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Europe

Description

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 (DNMT3A(R882H)) 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 DNMT3A(R882H) 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 DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) 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 DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.

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University of Copenhagen

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2016: Unused

Research area: Science & Technology

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2016: Level 2

Research area: Science & Technology

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Times Cited: 37

Field Citation Ratio (FCR): 9.63

Relative Citation ratio (RCR): 1.79

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Green, Accepted