Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis
| Autor: | Claudine Schiff, Bertrand Montpellier, Julie Agopian, Bertrand Nadel, Michèle Milili, Sandrine Roulland, Pierre Grenot, Pascal Gauduchon, Jean Navarro, Pierre Lebailly |
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| Přispěvatelé: | Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU) |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Follicular lymphoma
Chromosomal translocation Biochemistry Immunoglobulin D Translocation Genetic Pathogenesis MESH: Lymphoma Follicular 0302 clinical medicine Immunology and Allergy Memory B cell Lymphoma Follicular 0303 health sciences education.field_of_study biology MESH: G0 Phase Hematology MESH: Translocation Genetic Cell Transformation Neoplastic 030220 oncology & carcinogenesis MESH: Immunologic Memory Biomarker (medicine) [SDV.IMM]Life Sciences [q-bio]/Immunology MESH: B-Lymphocyte Subsets Naive B cell Immunology Population B-Lymphocyte Subsets Somatic hypermutation Resting Phase Cell Cycle 03 medical and health sciences medicine Humans education 030304 developmental biology Chromosomes Human Pair 14 MESH: Humans MESH: Clone Cells Brief Definitive Report Germinal center Cell Biology medicine.disease Molecular biology Lymphoma Clone Cells Immunoglobulin M MESH: Cell Transformation Neoplastic biology.protein MESH: Chromosomes Human Pair 14 Brief Definitive Reports MESH: Chromosomes Human Pair 18 Chromosomes Human Pair 18 Immunologic Memory |
| Zdroj: | The Journal of Experimental Medicine Journal of Experimental Medicine Journal of Experimental Medicine, 2006, 203 (11), pp.2425-31. ⟨10.1084/jem.20061292⟩ Journal of Experimental Medicine, Rockefeller University Press, 2006, 203 (11), pp.2425-31. ⟨10.1084/jem.20061292⟩ |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Follicular lymphoma (FL) is one of the most common B-cell lymphoma, and remains virtually incurable despite its relatively indolent nature. T(14;18)(q32;q21), the genetic hallmark and early initiating event of FL pathogenesis, is also present at low frequency (10−5–10−7) in blood from healthy individuals (HI), indicating that t(14;18) and the ensuing BCL2 overexpression is necessary but not sufficient for malignant transformation. It has long been assumed that in HI, t(14;18) is carried by circulating quiescent naïve B-cells, where its oncogenic potential would be restrained. Yet, several reports, including long-term persistence and immunomodulation of t(14;18)+ cells in lymphoma-free individuals, led us to question this model and investigate the status of circulating t(14;18)+ cells in HI. We first determined if t(14;18)+ cells are naïve B-cells by assessing class-switch recombination (CSR) on the translocated allele. Using 2 long-range PCR assays designed to amplify unswitched BCL2/Sμ and switched BCL2/Sg regions, DNA samples from 6 HI with t(14;18) were tested. Contrary to previous assumptions, our data clearly show that most peripheral t(14;18)+ cells already underwent CSR (n=5/6) and therefore that most t(14;18)+ cells are not naïve B-cells. Are they then memory B cells? Naïve and memory B cell subsets from 9 HI were isolated by cell sorting according to IgD and CD27 markers, and the rate of t(14;18) analyzed in each subset relatively to that of the total B cells. Strikingly, while the level of naïve t(14;18)+ cells remained at baseline for all individuals, memory B-cells tightly accounted for the wide modulation of t(14;18) frequencies observed between individuals. In addition, sequence analysis of t(14;18) clones revealed that this wide modulation was not due to the accumulation of clonally unrelated t(14;18) naïve B-cells, but rather to the clonal expansion of t(14;18)-bearing memory B-cells. To further define the t(14;18)+ cells, we next examined the repartition of the translocation in the IgD−/CD27+ and IgD+/CD27+ memory B-cell subsets. Unexpectedly, we found that the IgD+/CD27+ subset contained significantly higher rates of translocation than the IgD−/CD27+, both in terms of prevalence and frequency. Thus, while CSR is found in the majority of translocated alleles (~75%), most t(14;18)+ memory B cells have not switched their productive allele (~70%) and express an IgM/D. Most importantly, although atypical among physiological peripheral B-cells, this “allelic paradox” is a specific hallmark of FL, and suggests the presence of the same selective pressure in favor of sIgM expression on a B-cell population that is at the same time permanently driven to switch. In line with B-cell hyperplasia in BCL2 transgenic mice slowly progressing to low grade lymphoma, it is likely that “FL-like” cells in HI are rescued by BCL2 from apoptosis, and “frozen” at a differentiation stage in which constitutive AID expression drives continuous somatic hypermutation and CSR activity, two mechanisms conferring a high propensity for genomic instability. Altogether, our findings identify a novel intermediate step in early lymphomagenesis, and strongly impact both on the current understanding of disease progression from potent pre-malignant niches, and on the proper handling of t(14;18) frequency in blood as a potential early biomarker for lymphoma. |
| Databáze: | OpenAIRE |
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