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Rare occurrence of classical Hodgkin's disease as a T cell lymphoma.

Müschen M, Rajewsky K, Bräuninger A, Baur AS, Oudejans JJ, Roers A, Hansmann ML, Küppers R - J. Exp. Med. (2000)

Bottom Line: In a subset of cHD, however, H/RS cells expressing T cell-associated proteins may be candidates for alternative lineage derivation.Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers.In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Department of Immunology, Universität zu Köln, Germany. markus.mueschen@uni-koeln.de

ABSTRACT
Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is generally assumed that cHD homogenously represents a B cell lymphoma. In a subset of cHD, however, H/RS cells expressing T cell-associated proteins may be candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T cell phenotype were micromanipulated from three cases of cHD and analyzed by single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light chain (IgL) gene rearrangements, T cell receptor (TCR)-beta gene rearrangements, and germline configuration of the IgH and TCR-beta loci. H/RS cells from two cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas TCR-beta loci were in germline configuration. In contrast, H/RS cells from an additional case harbored clonal TCR-beta variable/diversity/joining (VDJ) and DJ gene rearrangements, whereas the IgH locus was in germline configuration on both alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers. In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

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Amplification of IgH gene and TCR-β gene rearrangements from H/RS cells. PCR strategies for amplification of PCR products which are specific for IgH (A) or TCR-β (B) germline configuration (i), DJ gene rearrangements (ii), and VDJ gene rearrangements (iii) are depicted. VH1-VH7 and Vβ1-Vβ24 represent the seven Ig VH gene families and the 24 TCR Vβ gene families; and JH1-JH6 and Jβ1.1-1.6 and Jβ2.1-2.7 indicate the Ig JH and the TCR Jβ genes, respectively. The IgH DJ (A, ii) and IgH VDJ (A, iii) rearrangements and TCR-β DJ (B, ii) and TCR-β VDJ (B, iii) rearrangements depict those amplified from cases I and III, respectively. Arrows indicate the PCR primers used (not to scale). (C) A fragment (codons 95–115) of the sequence alignment of the clonal TCR Vβ7.1–Dβ1–Jβ1.6 rearrangement amplified from single H/RS cells of case III is given. The germline sequence of Vβ7.1, Dβ1, and Jβ1.6 genes (top) is compared with the clonal sequence variants (A, B, and C) obtained from eight, two, and four H/RS cells of case III, respectively. The three sequence variants (A, B, and C) differ by single nucleotide substitutions in codons 98, 105, and 108 (complete sequence data are available from GenBank/EMBL/DDBJ under accession nos. AJ243645–AJ243647). (D) Sequence alignment of the clonal TCR Dβ1–Jβ1.4 rearrangement amplified from 14 H/RS cells of case III is given. In contrast to the clonal Vβ7.1 gene rearrangement (C), the Dβ1–Jβ1.4 gene rearrangement does not exhibit intraclonal diversity (complete sequence data is available from GenBank/EMBL/DDBJ under accession no. AJ243648).
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Figure 2: Amplification of IgH gene and TCR-β gene rearrangements from H/RS cells. PCR strategies for amplification of PCR products which are specific for IgH (A) or TCR-β (B) germline configuration (i), DJ gene rearrangements (ii), and VDJ gene rearrangements (iii) are depicted. VH1-VH7 and Vβ1-Vβ24 represent the seven Ig VH gene families and the 24 TCR Vβ gene families; and JH1-JH6 and Jβ1.1-1.6 and Jβ2.1-2.7 indicate the Ig JH and the TCR Jβ genes, respectively. The IgH DJ (A, ii) and IgH VDJ (A, iii) rearrangements and TCR-β DJ (B, ii) and TCR-β VDJ (B, iii) rearrangements depict those amplified from cases I and III, respectively. Arrows indicate the PCR primers used (not to scale). (C) A fragment (codons 95–115) of the sequence alignment of the clonal TCR Vβ7.1–Dβ1–Jβ1.6 rearrangement amplified from single H/RS cells of case III is given. The germline sequence of Vβ7.1, Dβ1, and Jβ1.6 genes (top) is compared with the clonal sequence variants (A, B, and C) obtained from eight, two, and four H/RS cells of case III, respectively. The three sequence variants (A, B, and C) differ by single nucleotide substitutions in codons 98, 105, and 108 (complete sequence data are available from GenBank/EMBL/DDBJ under accession nos. AJ243645–AJ243647). (D) Sequence alignment of the clonal TCR Dβ1–Jβ1.4 rearrangement amplified from 14 H/RS cells of case III is given. In contrast to the clonal Vβ7.1 gene rearrangement (C), the Dβ1–Jβ1.4 gene rearrangement does not exhibit intraclonal diversity (complete sequence data is available from GenBank/EMBL/DDBJ under accession no. AJ243648).

Mentions: To analyze individual micromanipulated cells for IgH, Igκ, Igλ, as well as TCR-β VDJ and DJ gene rearrangements or germline configuration of the IgH and TCR-β loci, whole genome preamplification 10 was performed. Aliquots from these reactions were then subjected to two rounds of seminested PCR amplification as described previously. For analysis of the IgH and TCR-β loci, three PCR strategies were applied (Fig. 2A and Fig. B), one of which targets IgH (Fig. 2 A, iii) or TCR-β (Fig. 2 B, iii) VDJ rearrangements, a second IgH (Fig. 2 A, ii) or TCR-β (Fig. 2 B, ii) DJ rearrangements, and a third detects germline configuration of either the IgH (Fig. 2 A, i) or the TCR-β (Fig. 2 B, i) locus. Rearranged VH, Vκ, and Vλ genes were amplified using family-specific leader or framework region V gene primers and two sets of JH, Jκ, and Jλ primers in a seminested approach 51112. DHJH rearrangements and germline configuration within the IgH locus were detected using seven DH family–specific primers and two sets of JH gene–specific primers in a seminested approach 5. In the case of germline configuration of the IgH locus, a 340-bp fragment was obtained with the DH7 primer, due to the close vicinity of the DH7-27 gene segment and JH1 (Fig. 2 A, i). DH family–specific primers were as follows: 5′-GTGTGCAGGCCTCRGTCTCTGTG-3′ for the DH1 gene family; 5′-GCACTGGGCTCAGAGTCCTCTC-3′ for the DH2 family; 5′-CCTCAGGTCAGCCCTGGACATC-3′ for the DH3 family; 5′-TGAGATCCCCAGGACGCAGCAC-3′ for the DH4 family; 5′-TCCCTGGGAAGCTCCTCCTGAC-3′ for the DH5 family; 5′-GACACCAGACAGAGGGGCAGGC-3′ for the DH6 family; and 5′-AGAGTGACTGGCAGGGTTGAGG-3′ for the DH7–27 gene. Amplification of TCR-β VDJ gene rearrangements was carried out as described previously using a panel of 24 Vβ family–specific primers and two sets of Jβ gene–specific primers in a seminested approach 13. Germline configuration was detected separately for both Cβ loci (Fig. 2 B, i) using primers binding to intronic sequences flanking the Dβ1 (5′-CCCCTTCGCCAAACAGCCTTA-3′ as forward, 5′-GAGTGAGGCAGAGGCATTCTGAAC-3′ as external reverse, and 5′-GCAGAGGCATTCTGAACCAAATTG-3′ as internal reverse primer) or the Dβ2 gene (5′-TCAGGGTGATGCATGTTCCAAGGA-3′ as forward, 5′-GGGACCCTGCAAGACCACAGCT-3′ as external reverse, and 5′-ACTCTTCCCACCTGGTAGCTGCAT-3′ as internal reverse primer). DβJβ rearrangements were amplified using the primers specific for intronic sequences in the upstream regions of the Dβ1 and the Dβ2 genes, together with primers specific for the Jβ1 or Jβ2 gene clusters, respectively (Fig. 2 B, ii).


Rare occurrence of classical Hodgkin's disease as a T cell lymphoma.

Müschen M, Rajewsky K, Bräuninger A, Baur AS, Oudejans JJ, Roers A, Hansmann ML, Küppers R - J. Exp. Med. (2000)

Amplification of IgH gene and TCR-β gene rearrangements from H/RS cells. PCR strategies for amplification of PCR products which are specific for IgH (A) or TCR-β (B) germline configuration (i), DJ gene rearrangements (ii), and VDJ gene rearrangements (iii) are depicted. VH1-VH7 and Vβ1-Vβ24 represent the seven Ig VH gene families and the 24 TCR Vβ gene families; and JH1-JH6 and Jβ1.1-1.6 and Jβ2.1-2.7 indicate the Ig JH and the TCR Jβ genes, respectively. The IgH DJ (A, ii) and IgH VDJ (A, iii) rearrangements and TCR-β DJ (B, ii) and TCR-β VDJ (B, iii) rearrangements depict those amplified from cases I and III, respectively. Arrows indicate the PCR primers used (not to scale). (C) A fragment (codons 95–115) of the sequence alignment of the clonal TCR Vβ7.1–Dβ1–Jβ1.6 rearrangement amplified from single H/RS cells of case III is given. The germline sequence of Vβ7.1, Dβ1, and Jβ1.6 genes (top) is compared with the clonal sequence variants (A, B, and C) obtained from eight, two, and four H/RS cells of case III, respectively. The three sequence variants (A, B, and C) differ by single nucleotide substitutions in codons 98, 105, and 108 (complete sequence data are available from GenBank/EMBL/DDBJ under accession nos. AJ243645–AJ243647). (D) Sequence alignment of the clonal TCR Dβ1–Jβ1.4 rearrangement amplified from 14 H/RS cells of case III is given. In contrast to the clonal Vβ7.1 gene rearrangement (C), the Dβ1–Jβ1.4 gene rearrangement does not exhibit intraclonal diversity (complete sequence data is available from GenBank/EMBL/DDBJ under accession no. AJ243648).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195757&req=5

Figure 2: Amplification of IgH gene and TCR-β gene rearrangements from H/RS cells. PCR strategies for amplification of PCR products which are specific for IgH (A) or TCR-β (B) germline configuration (i), DJ gene rearrangements (ii), and VDJ gene rearrangements (iii) are depicted. VH1-VH7 and Vβ1-Vβ24 represent the seven Ig VH gene families and the 24 TCR Vβ gene families; and JH1-JH6 and Jβ1.1-1.6 and Jβ2.1-2.7 indicate the Ig JH and the TCR Jβ genes, respectively. The IgH DJ (A, ii) and IgH VDJ (A, iii) rearrangements and TCR-β DJ (B, ii) and TCR-β VDJ (B, iii) rearrangements depict those amplified from cases I and III, respectively. Arrows indicate the PCR primers used (not to scale). (C) A fragment (codons 95–115) of the sequence alignment of the clonal TCR Vβ7.1–Dβ1–Jβ1.6 rearrangement amplified from single H/RS cells of case III is given. The germline sequence of Vβ7.1, Dβ1, and Jβ1.6 genes (top) is compared with the clonal sequence variants (A, B, and C) obtained from eight, two, and four H/RS cells of case III, respectively. The three sequence variants (A, B, and C) differ by single nucleotide substitutions in codons 98, 105, and 108 (complete sequence data are available from GenBank/EMBL/DDBJ under accession nos. AJ243645–AJ243647). (D) Sequence alignment of the clonal TCR Dβ1–Jβ1.4 rearrangement amplified from 14 H/RS cells of case III is given. In contrast to the clonal Vβ7.1 gene rearrangement (C), the Dβ1–Jβ1.4 gene rearrangement does not exhibit intraclonal diversity (complete sequence data is available from GenBank/EMBL/DDBJ under accession no. AJ243648).
Mentions: To analyze individual micromanipulated cells for IgH, Igκ, Igλ, as well as TCR-β VDJ and DJ gene rearrangements or germline configuration of the IgH and TCR-β loci, whole genome preamplification 10 was performed. Aliquots from these reactions were then subjected to two rounds of seminested PCR amplification as described previously. For analysis of the IgH and TCR-β loci, three PCR strategies were applied (Fig. 2A and Fig. B), one of which targets IgH (Fig. 2 A, iii) or TCR-β (Fig. 2 B, iii) VDJ rearrangements, a second IgH (Fig. 2 A, ii) or TCR-β (Fig. 2 B, ii) DJ rearrangements, and a third detects germline configuration of either the IgH (Fig. 2 A, i) or the TCR-β (Fig. 2 B, i) locus. Rearranged VH, Vκ, and Vλ genes were amplified using family-specific leader or framework region V gene primers and two sets of JH, Jκ, and Jλ primers in a seminested approach 51112. DHJH rearrangements and germline configuration within the IgH locus were detected using seven DH family–specific primers and two sets of JH gene–specific primers in a seminested approach 5. In the case of germline configuration of the IgH locus, a 340-bp fragment was obtained with the DH7 primer, due to the close vicinity of the DH7-27 gene segment and JH1 (Fig. 2 A, i). DH family–specific primers were as follows: 5′-GTGTGCAGGCCTCRGTCTCTGTG-3′ for the DH1 gene family; 5′-GCACTGGGCTCAGAGTCCTCTC-3′ for the DH2 family; 5′-CCTCAGGTCAGCCCTGGACATC-3′ for the DH3 family; 5′-TGAGATCCCCAGGACGCAGCAC-3′ for the DH4 family; 5′-TCCCTGGGAAGCTCCTCCTGAC-3′ for the DH5 family; 5′-GACACCAGACAGAGGGGCAGGC-3′ for the DH6 family; and 5′-AGAGTGACTGGCAGGGTTGAGG-3′ for the DH7–27 gene. Amplification of TCR-β VDJ gene rearrangements was carried out as described previously using a panel of 24 Vβ family–specific primers and two sets of Jβ gene–specific primers in a seminested approach 13. Germline configuration was detected separately for both Cβ loci (Fig. 2 B, i) using primers binding to intronic sequences flanking the Dβ1 (5′-CCCCTTCGCCAAACAGCCTTA-3′ as forward, 5′-GAGTGAGGCAGAGGCATTCTGAAC-3′ as external reverse, and 5′-GCAGAGGCATTCTGAACCAAATTG-3′ as internal reverse primer) or the Dβ2 gene (5′-TCAGGGTGATGCATGTTCCAAGGA-3′ as forward, 5′-GGGACCCTGCAAGACCACAGCT-3′ as external reverse, and 5′-ACTCTTCCCACCTGGTAGCTGCAT-3′ as internal reverse primer). DβJβ rearrangements were amplified using the primers specific for intronic sequences in the upstream regions of the Dβ1 and the Dβ2 genes, together with primers specific for the Jβ1 or Jβ2 gene clusters, respectively (Fig. 2 B, ii).

Bottom Line: In a subset of cHD, however, H/RS cells expressing T cell-associated proteins may be candidates for alternative lineage derivation.Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers.In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Department of Immunology, Universität zu Köln, Germany. markus.mueschen@uni-koeln.de

ABSTRACT
Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is generally assumed that cHD homogenously represents a B cell lymphoma. In a subset of cHD, however, H/RS cells expressing T cell-associated proteins may be candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T cell phenotype were micromanipulated from three cases of cHD and analyzed by single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light chain (IgL) gene rearrangements, T cell receptor (TCR)-beta gene rearrangements, and germline configuration of the IgH and TCR-beta loci. H/RS cells from two cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas TCR-beta loci were in germline configuration. In contrast, H/RS cells from an additional case harbored clonal TCR-beta variable/diversity/joining (VDJ) and DJ gene rearrangements, whereas the IgH locus was in germline configuration on both alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers. In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

Show MeSH
Related in: MedlinePlus