Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Montesinos‐Rongen, Manuel; Brunn, Anna; Bentink, Stefan; Basso, Katia; Lim, Wei Keat; Klapper, Wolfram; Schaller, Carlo; Reifenberger, Guido; Rubenstein, James L.; Wiestler, Otmar D.; Spang, Rainer; Dalla‐Favera, Riccardo; Siebert, Reiner; Deckert, Martina

doi:10.1038/sj.leu.2405019

Cited by 160 publications

(135 citation statements)

References 18 publications

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“…1-18), except for PCNSL 19, gene expression profiles were available (GEO database 23 GSE6047 24 ). For all mRNAs in the minimal common regions (MCR) detected by SNP, corresponding tags on the HG-U95Av2 platform (Affymetrix) were evaluated for mRNA expression.…”

Section: Correlation Of Minimal Common Regions With Gene Expression Pmentioning

confidence: 99%

“…For all mRNAs in the minimal common regions (MCR) detected by SNP, corresponding tags on the HG-U95Av2 platform (Affymetrix) were evaluated for mRNA expression. Normalized gene expression profiles 24 were analyzed in geWorkbench (http://wiki.c2b2.columbia.edu/workbench/index.php/Home). After replacing all values below 100 by 100 (background noise correction) and log2 transformation, mRNAs of tumors harboring these MCRs were compared with those without genetic alterations in these loci as evidenced by SNP analysis.…”

Section: Correlation Of Minimal Common Regions With Gene Expression Pmentioning

confidence: 99%

“…24 In 17 of 21 MCRs, at least one mRNA could be analyzed with respect to a differential expression between PCNSL with and without any alteration in the respective MCR. Only four MCRs showed a differential expression of at least one mRNA.…”

Section: Comparison Of Mcr With Gene Expression Profilesmentioning

confidence: 99%

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Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

et al. 2009

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To determine the pattern of genetic alterations in primary central nervous system lymphomas (PCNSL), 19 PCNSL were studied by high-density single-nucleotide polymorphism arrays. Recurrent losses involved 6p21.32, 6q21, 8q12-12.2, 9p21.3, 3p14.2, 4q35.2, 10q23.21 and 12p13.2, whereas gains involved 18q21-23, 19q13.31, 19q13.43 and the entire chromosomes X and 12. Partial uniparental disomies (pUPDs) were identified in 6p and 9p21.3. These genomic alterations affected the HLA locus, the CDKN2A/p16, CDKN2B/p15 and MTAP, as well as the PRDM1, FAS, MALT1, and BCL2 genes. Increased methylation values of the CDKN2A/p16 promoter region were detected in 75% (6/8) PCNSL. Gene expression profiling showed 4/21 (20%) minimal common regions of imbalances to be associated with a differential mRNA expression affecting the FAS, STAT6, CD27, ARHGEF6 and SEPT6 genes. Collectively, this study unraveled novel genomic imbalances and pUPD with a high resolution in PCNSL and identified target genes of potential relevance in the pathogenesis of this lymphoma entity.

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Section: Correlation Of Minimal Common Regions With Gene Expression Pmentioning

confidence: 99%

Section: Correlation Of Minimal Common Regions With Gene Expression Pmentioning

confidence: 99%

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Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

et al. 2009

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“…Because such ongoing hypermutation and BCL-6 expression are considered as germinal center (GC) markers, it has been postulated that the cell of origin of PCNSL passes through the GC microenvironment and that these neoplasms correspond to the GCB subgroup as defined for DLBCL. However, recent immunoprofiling [16] and gene expression studies using cDNA microarrays [17,18] demonstrated that PCNSL may exhibit characteristics associated with both the ABC and GCB subtypes. Thus, PCNSLs may correspond to an overlapping B-cell differentiation time slot, that is, the late GC/early post-GC stage.…”

Section: Pathology and Pathogenesismentioning

confidence: 99%

Primary CNS Lymphoma in Immunocompetent Patients

et al. 2009

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Primary central nervous system lymphoma (PCNSL) constitutes a rare group of extranodal non-Hodgkin's lymphomas (NHLs), primarily of B cell origin, whose incidence has markedly increased in the last three decades. Immunodeficiency is the main risk factor, but the large majority of patients are immunocompetent. Recent evidence suggests a specific tumorigenesis that may explain their particular clinical behavior compared with systemic NHL. The addition of i.v. high-dose methotrexate (MTX) chemotherapy to whole-brain radiotherapy (WBRT) has considerably improved the prognosis, leading to a threefold longer median survival time compared with WBRT alone and represents the current standard of care. However, this combined treatment exposes the patient, especially the elderly, to a high risk for delayed neurotoxicity. In the older population (>60 years), there is growing evidence that MTX-based chemotherapy alone as initial treatment is the best approach to achieve effective tumor control without compromising patient quality of life. In the younger population, the risk for neurotoxicity is much lower, and this strategy is controversial because it may be associated with higher relapse rates. Future efforts should focus on the development of new polychemotherapy regimens allowing the reduction or deferral of WBRT in order to minimize the risk for delayed neurotoxicity. In this setting, intensive chemotherapy with autologous blood stem cell transplantation was recently demonstrated to be feasible and efficient as salvage therapy and is currently being evaluated as part of primary treatment. This review highlights the recent advances in the pathogenesis and treatment of PCNSL in the immunocompetent population.

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“…Its exclusive manifestation in the CNS remains a mystery. PCNSL cells correspond to late germinal center (GC) exit B cells with surface IgM expression (3,4); they are characterized by rearranged and somatically mutated Ig genes with a high Ig genemutation frequency (5)(6)(7)(8). Collectively, these features, which indicate participation of the tumor cells in a prolonged GC reaction, as well as the restricted Ig VH gene repertoire with a biased usage of the IGVH4-34 gene segment and evidence for ongoing somatic hypermutation (SHM), provide strong evidence for Ag selection for expression of a functional BCR (5,8,9).…”

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confidence: 99%

Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins

Montesinos‐Rongen

Purschke

Brunn

et al. 2015

The Journal of Immunology

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Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS.

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Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Cited by 160 publications

References 18 publications

Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

Primary CNS Lymphoma in Immunocompetent Patients

Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins

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