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Immunology

Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Giorgio Cattoretti, Jonathan Mandelbaum, Nancy Lee, Alicia H. Chaves, Ashley M. Mahler, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci and A. John MacLennan
Giorgio Cattoretti
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Jonathan Mandelbaum
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Nancy Lee
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Alicia H. Chaves
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Ashley M. Mahler
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Amy Chadburn
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Riccardo Dalla-Favera
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Laura Pasqualucci
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A. John MacLennan
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DOI: 10.1158/0008-5472.CAN-09-1110 Published November 2009
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    Figure 1.

    Histopathology of DLBCL in S1P2−/− mice. Representative DLBCL, featuring H&E staining (note the large tumor cells in the Wright-Giemsa–stained touch preparation in the inset). These tumor cells display positive BCL6 (dark blue), B220 (purple gray), and PNA (reddish brown) staining, and negative IRF4 (dark blue) and CD138 (dark blue) staining. The lymph node is totally replaced by diffuse large cell lymphoma proliferation, containing lymphocytes and inflammatory cells (BCL6, B220, and PNA negative, and IRF4 and CD138 positive). The PNA-stained section also received a light blue nuclear counterstain. Scale bars, 10 μm (bottom) and 1 μm (top).

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    Figure 2.

    DLBCL immunophenotype in S1P2−/− mice. A, surface immunophenotype by FCM of a representative DLBCL from a S1P2−/− mouse and a histologically normal spleen from a littermate control S1P2+/+ mouse. Note the low/absent surface Ig, the loss of CD23, and the absence of CD138 in the DLBCL sample. B, AID expression in representative DLBCL from S1P2−/− mice, compared with purified normal GC B cells from two S1P2−/− and one S1P2+/+ mice. Mouse lung tissue was used as a negative control for the AID RT-PCR.

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    Figure 3.

    Clonal rearrangements of the IgH locus and evidence of SHM in DLBCL from S1P2−/− mice. A, Southern blot analysis of EcoRI-digested DNA from representative S1P2−/− DLBCLs, and control tail DNA, hybridized with a murine JH region probe. The germline immunoglobulin heavy chain EcoRI fragment is ∼6.5 Kb (arrow). *, clonal rearrangements of the IgH gene in the tumors analyzed. The predominant germline band observed in some tumors is most likely due to the presence of infiltrating normal cells (see text). B, mutation analysis of clonally rearranged IgV genes in lymphomas from representative S1P2−/− animals. Note that although Southern blot analysis in tumors #246 and #297 suggests the presence of two distinct clones, only one rearranged allele could be successfully amplified, possibly due to the usage of a less common V gene family member not recognized by the primers used, or to the presence of mutations in the primer binding site. C, nucleotide sequence alignment of the rearranged IgV gene from S1P2−/− DLBCL #245 (as obtained by direct sequencing) with the germline VH7183 and JH region. Dashes, sequence identities; the indicated nucleotides correspond to mutations. Note that since direct sequencing only detects clonally represented events, the observed mutations can be unequivocally attributed to the malignant clone.

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    Figure 4.

    Morphometric analysis of splenic GC formation in S1P2−/− mice. A, unimmunized mice; total area of BCL6+ aggregates in each size range [measured in pixels (1,000 pixels = 1 Kpx)] normalized for spleen section area. Inset, percentage of splenic B220+ PNA+ GC cells in old, unimmunized control and knockout mice measured by flow cytometry. The difference is significant (P < 0.0015). B, unimmunized mice; number of BCL6+ aggregates per spleen section area, calculated as described in A. The numbers presented are per average spleen section. *, ANOVA analyses indicated that both the size and number of >2 Kpx aggregates are significantly (P < 0.05) increased in S1P2−/− spleens. C, number and area of the GC aggregates in SRBC-immunized mice. Note the expected increase in larger aggregates for immunized control and knockout mice compared with values for unimmunized mice in A and B. n = 7 young control, 3 young S1P2−/−, 4 old control, 3 old S1P2−/−. Columns, mean; bars, SEM.

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    Figure 5.

    Mutational analysis of the S1P2 gene in human DLBCL. Top, S1P2 genomic locus with untranslated (empty boxes) and translated (filled boxes) exons; arrow, the transcriptional start site per GeneBank accession no. NM_004230. The region amplified for analysis is expanded in the bottom and aligned to sequences of mutated DLBCL cases (one line = two alleles), where each small segment represents a 25-bp interval and position +1 corresponds to the first nucleotide of the reference mRNA. Ovals, single basepair substitutions; brackets, deletions; triangles, insertions.

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  • Table 1.

    Mutational analysis of the S1P2 5′ sequences in DLBCL

    TotalCell linesPrimary cases
    n of cases mutated/tested (%) 28/106 (26%)5/20 (25%)23/86 (27%)
    Mutation frequency*0.17%0.18%0.17%
    n of single bp substitutions1052184
    n of deletions+duplications918
    Transitions/transversions (ratio)61/44 (1.38)16/5 (3.2)45/39 (1.15)
    G+C/A+T mutations81/2417/464/20
    • ↵*Calculated in the mutated cases only, considering two alleles/sample (1,200 bp × 2).

Additional Files

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    • Supplementary Figure 1
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    • Supplementary Figure 5
    • Supplementary Figure 6
    • Supplementary Figure 7
    • Supplementary Methods
    • Supplementary Tables 1-3
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Cancer Research: 69 (22)
November 2009
Volume 69, Issue 22
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Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation
Giorgio Cattoretti, Jonathan Mandelbaum, Nancy Lee, Alicia H. Chaves, Ashley M. Mahler, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci and A. John MacLennan
Cancer Res November 15 2009 (69) (22) 8686-8692; DOI: 10.1158/0008-5472.CAN-09-1110

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Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation
Giorgio Cattoretti, Jonathan Mandelbaum, Nancy Lee, Alicia H. Chaves, Ashley M. Mahler, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci and A. John MacLennan
Cancer Res November 15 2009 (69) (22) 8686-8692; DOI: 10.1158/0008-5472.CAN-09-1110
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