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B-cell tumor development in Tet2-deficient mice

Mouly, Enguerran, Ghamlouch, Hussein, Della-Valle, Veronique, Scourzic, Laurianne, Quivoron, Cyril, Roos-Weil, Damien, Pawlikowska, Patrycja, Saada, Véronique, Diop, M’Boyba K., Lopez, Cécile K., Fontenay, Michaela, Dessen, Philippe, Touw, Ivo P., Mercher, Thomas, Aoufouchi, Said, Bernard, Olivier A.·2018·Blood Advances
DOI 10.1182/bloodadvances.2017014118
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Abstract

Key Points: Tet2 is a tumor suppressor in B cells. Loss of Tet2 in B cells leads to age-dependent transformation that requires AID.

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Crossref · 10.1182/bloodadvances.2017014118

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Figures

Figure 1 Tet2 deficiency leads to the accumulation of clonal B220 low B-cell population in a cell-autonomous fashion. (A) Monthly monitoring of blood cell count in Tet2 CD19-Cre 2 and Tet2 CD19-Cre 1 mice. *** P , .001. (B) Monthly monitoring of CD19 1 B220 low abnormal cell population in the blood of Tet2 CD19-Cre 2 and Tet2 CD19-Cre 1 mice (left panel). Significance was tested using an unpaired Student t test. Time-dependent representation of the proportion of the B220 low population within the circulating B cells (CD19 1 ) in the same mice as in panel A (right panel). Significance was tested using an unpaired Student t test. (C) Spleen weight of sacrificed mice at various time points was measured for both types of mice. Significance was tested using an unpaired Student t test. (D) Immunostaining of total splenocytes (polychromatic dot plot) from a representative sick Tet2 CD19-Cre 1 mouse (same genotypes as above). Splenocytes were first stained with B220 and CD19 to define the B220 1 and B220 low population of CD19 1 cells (left polychromatic dot plot). Other dot plots show B220 expression together with the indicated antibody on the x-axis of the overlaid B220 1 CD19 1 population (green) and B220 low CD19 1 population (violet). (E) Analyses of BCR rearrangement clonality in abnormal Tet2 CD19-Cre 1 B cells. V-J junctions were PCR-amplified from cDNA of sorted B cells using VH family primers (VH1, VH2, VH3, VH5, VH6, and VH7, as indicated) and conjugated consensus JH primer 22 to assess the IgH CDR3 diversity. Top panels show Results shown are obtained from sorted Tet2 CD19Cre 2 B splenocytes (B220 1 CD19 1 ) (top) and from age-matched Tet2 CD19-Cre 1 sorted abnormal B cells (B220 low CD19 1 ) (bottom). (F) Transcription of selected genes important for B-cell differentiation differs between normal WT and Tet2 -deficient tumor B cells. Histograms show quantitative reverse transcription (qRT) -PCR analysis results DD CT-normalized by Abl1 expression levels. Results are an average of 3 independent duplicate experiments. The differences were validated in an extension cohort for 8 of the 11 genes. Significance was tested using the Mann-Whitney U test. * P , .05; ** P , .01; *** P , .001. ns, not significant.
Figure 1 Tet2 deficiency leads to the accumulation of clonal B220 low B-cell population in a cell-autonomous fashion. (A) Monthly monitoring of blood cell count in Tet2 CD19-Cre 2 and Tet2 CD19-Cre 1 mice. *** P , .001. (B) Monthly monitoring of CD19 1 B220 low abnormal cell population in the blood of Tet2 CD19-Cre 2 and Tet2 CD19-Cre 1 mice (left panel). Significance was tested using an unpaired Student t test. Time-dependent representation of the proportion of the B220 low population within the circulating B cells (CD19 1 ) in the same mice as in panel A (right panel). Significance was tested using an unpaired Student t test. (C) Spleen weight of sacrificed mice at various time points was measured for both types of mice. Significance was tested using an unpaired Student t test. (D) Immunostaining of total splenocytes (polychromatic dot plot) from a representative sick Tet2 CD19-Cre 1 mouse (same genotypes as above). Splenocytes were first stained with B220 and CD19 to define the B220 1 and B220 low population of CD19 1 cells (left polychromatic dot plot). Other dot plots show B220 expression together with the indicated antibody on the x-axis of the overlaid B220 1 CD19 1 population (green) and B220 low CD19 1 population (violet). (E) Analyses of BCR rearrangement clonality in abnormal Tet2 CD19-Cre 1 B cells. V-J junctions were PCR-amplified from cDNA of sorted B cells using VH family primers (VH1, VH2, VH3, VH5, VH6, and VH7, as indicated) and conjugated consensus JH primer 22 to assess the IgH CDR3 diversity. Top panels show Results shown are obtained from sorted Tet2 CD19Cre 2 B splenocytes (B220 1 CD19 1 ) (top) and from age-matched Tet2 CD19-Cre 1 sorted abnormal B cells (B220 low CD19 1 ) (bottom). (F) Transcription of selected genes important for B-cell differentiation differs between normal WT and Tet2 -deficient tumor B cells. Histograms show quantitative reverse transcription (qRT) -PCR analysis results DD CT-normalized by Abl1 expression levels. Results are an average of 3 independent duplicate experiments. The differences were validated in an extension cohort for 8 of the 11 genes. Significance was tested using the Mann-Whitney U test. * P , .05; ** P , .01; *** P , .001. ns, not significant.CC-BY-NC-ND · From the PDF
Figure 2 Normal steady-state early B-cell development in Tet2 -deficent mice. (A) qRT-PCR analysis transcription levels of the 3 murine Tet genes normalized by Abl1 expression. Results are the average of 3 independent experiments performed in duplicate. (B) Bone marrow B-cell development analysis. Total BM cells were analyzed for B220 and IgM expression. Immature B cells B220 low IgM 1 and mature B cells B220 1 IgM 1 are indicated. Then CD43 expression was evaluated in gated B220 1 IgM 2 cells to define pre-B (CD43 2 ) and pro-B (CD43 1 ) populations; finally, the more immature Hardy fractions (Fr.A CD24 2 Bp1 2 ; Fr.B: CD24 1 Bp1 2 ; and Fr.CC 9 : CD24 1 Bp1 1 ) were analyzed in the pro-B-cell gate. The genotypes of the analyzed mice are indicated on the left side. (C) Average percentage of cell populations. (Left) Total B220 1 cells (each dot represents an independent mouse). (Middle) Average percentage of the indicated population in the B-cell compartment for each genotype. (Right) Hardy fraction percentage inside the pro-B-cell compartment. Genotypes are indicated ( Tet2 1 / 1 mice, n 5 6; Tet2 2 / 2 mice, n 5 8). Im-B, immature B cells B220 low IgM 1 ; Mat-B, mature B cells B220 1 IgM 1 .
Figure 2 Normal steady-state early B-cell development in Tet2 -deficent mice. (A) qRT-PCR analysis transcription levels of the 3 murine Tet genes normalized by Abl1 expression. Results are the average of 3 independent experiments performed in duplicate. (B) Bone marrow B-cell development analysis. Total BM cells were analyzed for B220 and IgM expression. Immature B cells B220 low IgM 1 and mature B cells B220 1 IgM 1 are indicated. Then CD43 expression was evaluated in gated B220 1 IgM 2 cells to define pre-B (CD43 2 ) and pro-B (CD43 1 ) populations; finally, the more immature Hardy fractions (Fr.A CD24 2 Bp1 2 ; Fr.B: CD24 1 Bp1 2 ; and Fr.CC 9 : CD24 1 Bp1 1 ) were analyzed in the pro-B-cell gate. The genotypes of the analyzed mice are indicated on the left side. (C) Average percentage of cell populations. (Left) Total B220 1 cells (each dot represents an independent mouse). (Middle) Average percentage of the indicated population in the B-cell compartment for each genotype. (Right) Hardy fraction percentage inside the pro-B-cell compartment. Genotypes are indicated ( Tet2 1 / 1 mice, n 5 6; Tet2 2 / 2 mice, n 5 8). Im-B, immature B cells B220 low IgM 1 ; Mat-B, mature B cells B220 1 IgM 1 .CC-BY-NC-ND · From the PDF
Image 3
CC-BY-NC-ND · From the PDF
Figure 4 Tet2-deficient abnormal B cells share features with human B-cell
Figure 4 Tet2-deficient abnormal B cells share features with human B-cellCC-BY-NC-ND · From the PDF
Figure 5 Tet2 -deficient abnormal B-cells are BCR-inhibition sensitive. (A) Abnormal B-cell phenotype and frequencies in the peripheral blood of mice transplanted with TCL1A transduced Tet2 1 / 1 or Tet2 2 / 2 hematopoietic progenitors. Dot plots show a representative example of B220 and CD19 expression analysis in the GFP 1 total leukocytes 4 months after transplantation. Diagrams depict the average percentages of the B220 low population in the blood of n 5 3 mice per group 4 months after transplantation. Error bars represent means 6 standard deviation (SD). (B) Tet2 deficiency enhances the tumor phenotype of TCL1A (GFP 1 ) overexpressing B cells, as is shown by abnormal cell numbers and CD5 membrane expression level. (Upper left) B220 CD19 expression in gated GFP 1 cells expressing TCL1A in primary and secondary recipient mice engrafted with BM cells overexpressing TCL1A in a Tet2 1 / 1 or Tet2 2 / 2 background. (Lower left) Average 6 SD of the median fluorescence intensity of the B220 antigen at the cell surface of CD19 1 B cells in each group. (Upper right) Expression of CD5 and IgM on the gated B cells as in the upper-left contour plots. A representative contour plot is shown for each group. (Lower right)
Figure 5 Tet2 -deficient abnormal B-cells are BCR-inhibition sensitive. (A) Abnormal B-cell phenotype and frequencies in the peripheral blood of mice transplanted with TCL1A transduced Tet2 1 / 1 or Tet2 2 / 2 hematopoietic progenitors. Dot plots show a representative example of B220 and CD19 expression analysis in the GFP 1 total leukocytes 4 months after transplantation. Diagrams depict the average percentages of the B220 low population in the blood of n 5 3 mice per group 4 months after transplantation. Error bars represent means 6 standard deviation (SD). (B) Tet2 deficiency enhances the tumor phenotype of TCL1A (GFP 1 ) overexpressing B cells, as is shown by abnormal cell numbers and CD5 membrane expression level. (Upper left) B220 CD19 expression in gated GFP 1 cells expressing TCL1A in primary and secondary recipient mice engrafted with BM cells overexpressing TCL1A in a Tet2 1 / 1 or Tet2 2 / 2 background. (Lower left) Average 6 SD of the median fluorescence intensity of the B220 antigen at the cell surface of CD19 1 B cells in each group. (Upper right) Expression of CD5 and IgM on the gated B cells as in the upper-left contour plots. A representative contour plot is shown for each group. (Lower right)CC-BY-NC-ND · From the PDF

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Citations

Cites

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Metadata

Authors
Mouly, E., Ghamlouch, H., Della-Valle, V., Scourzic, L., Quivoron, C., Roos-Weil, D., Pawlikowska, P., Saada, V., Diop, M. K., Lopez, C. K., Fontenay, M., Dessen, P., Touw, I. P., Mercher, T., Aoufouchi, S., & Bernard, O. A.
Affiliations
  • INSERM, Unité Mixte de Recherche (UMR)1170, Institut Gustave Roussy, Villejuif, France;
  • Institut Gustave Roussy, Villejuif, France;
  • Département Développement, Reproduction, Cancer, Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France; and
  • Department of Hematology, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
ORCID
Ghamlouch, Hussein
Venue
Blood Advances
Publisher
American Society of Hematology
Published
2018-03-26
Volume
2
Issue
6
Pages
703-714
ISSN
  • 2473-9529
  • 2473-9537
DOI
10.1182/bloodadvances.2017014118
Cited by
58
References
9
Language
en

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