B-cell tumor development in Tet2-deficient mice.

Abstract

The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

• Authors: Enguerran Mouly, Hussein Ghamlouch, Veronique Della-Valle, Laurianne Scourzic, Cyril Quivoron, Damien Roos-Weil, Patrycja Pawlikowska, Véronique Saada, M'Boyba K Diop, Cécile K Lopez, Michaela Fontenay, Philippe Dessen, Ivo P Touw, Thomas Mercher, Said Aoufouchi, Olivier A Bernard
• Journal: Blood advances (Blood Adv) Vol. 2 Issue 6 Pg. 703-714 (03 27 2018) ISSN: 2473-9537 [Electronic] United States
• PMID: 29581109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Biomarkers
• DNA-Binding Proteins
• Proto-Oncogene Proteins
• Receptors, Antigen, B-Cell
• Dioxygenases
• Tet2 protein, mouse

Topics

• Alleles
• Animals
• B-Lymphocytes
• Biomarkers
• Cell Survival
• DNA-Binding Proteins (deficiency)
• Dioxygenases
• Flow Cytometry
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• Leukemia, B-Cell (genetics, metabolism, pathology)
• Lymphoma, B-Cell (genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• Mutation
• Proto-Oncogene Proteins (deficiency)
• Receptors, Antigen, B-Cell (metabolism)