Long-term clonal persistence and evolution of t(14;18)-bearing B cells in healthy individuals

Roulland, Sandrine; Lebailly, Pierre; Lécluse, Yannick; Heutte, Natacha; Nadel, Bertrand; Gauduchon, Pascal

doi:10.1038/sj.leu.2404035

Cited by 77 publications

(72 citation statements)

References 9 publications

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“…At least some of the t(14;18)-bearing clones are likely to be memory cells rather than naive B-cells, because most BCL-2/IgH clones are long-lived and persist over several years in the periphery ( 30 ). Chronic hepatitis C virus infection can promote either the occurrence or maintenance of t(14;18) + clones ( 31 ).…”

Section: Downloaded Frommentioning

confidence: 99%

Chromosome Translocations in Workers Exposed to Benzene

McHale

Lan²,

Corso³

et al. 2008

JNCI Monographs

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Epidemiological studies indicate that benzene exposure is associated with an increased risk of human leukemia and lymphoma ( 1 , 2 ). Chromosomal translocations are thought to be initiating events in leukemia and lymphoma, and specific translocations are used as markers of diagnosis, disease progression, and relapse. As benzene is thought to act by producing chromosomal aberrations and altered cell differentiation ( 3 ), we investigated the possibility of using circulating levels of two acute myeloid leukemia (AML) -associated translocations, t(8;21) ( 4 ) and t(15;17) ( 5 ), and a follicular lymphoma -associated translocation, t(14;18) ( 6 ), as biomarkers of early effect for benzene. Evidence for the occurrence of these translocations in normal individuals is limited, with t(8;21) detected in 1 in 496 cord blood samples ( 7 ) and t(15;17) detected in healthy volunteers ( 8 ). As recently reviewed ( 9 ), the prevalence of t(14;18) in peripheral blood lymphocytes of healthy donors is relatively high at ~ 50% (range 8% -80% depending on the polymerase chain reaction (PCR) methodology employed and target cell population) ( 9 -13 ) and rises with smoking ( 14 ), but the correlation between frequency and age remains unclear ( 13 , 15 ). The biological consequences of these aberrations in healthy individuals are yet to be understood. One possibility is that the frequency of translocationpositive cells represents a biomarker of early effect for hematopoietic carcinogens which could correlate with the cumulative risk of developing t(14;18)-related follicular lymphoma and t(8;21)-and t(15;17)-related AML, and perhaps other cancers.The two principal technologies for detection of specifi c chromosome translocations are fl uorescence in situ hybridization (FISH) and real-time PCR. FISH distinguishes individual chromosomes by hybridization with sequence-specifi c, chromosomepainting probes labeled with spectrally nonoverlapping fl uorophores. In real-time quantitative PCR (qPCR), a fl uorescently labeled probe is hybridized to the amplifi cation target, and fl uorescent signal proportional to the input DNA/cDNA is generated during amplifi cation, thereby allowing quantifi cation. qPCR assays the whole peripheral blood mononuclear cell (PBMC) population in G 0 , whereas FISH examines a culture-modifi ed popula tion [consisting of mainly mature T lymphocytes stimulated by the mitogen phytohemagglutinin that have gone through two cell divi sions ( 16 )]. The two methods also generate different estimates of t(14;18) translocation levels with FISH detecting all possible t(14;18) breakpoints and the real-time assay described here only detecting breakpoints occurring in the major breakpoint region (MBR) of the BCL-2 gene. Although it was previously thought that the majority of BCL-2 breakpoints occur in the MBR ( 17 ), it has been shown more recently that many breakpoints occur outside of the MBR and the minor cluster region ( 18 ). The ability of FISH to detect more translocation breakpoints is offset by its lower relative sensit...

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Section: Downloaded Frommentioning

confidence: 99%

Chromosome Translocations in Workers Exposed to Benzene

McHale

Lan²,

Corso³

et al. 2008

JNCI Monographs

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“…5 Furthermore, studies tracking these cells over more than 10 years have demonstrated the persistence and evolution of a major, dominant proliferating (14;18)-carrying B-cell clone within a given individual. 6,7 Two anecdotal reports also described that the t(14;18)-B-cell clone represented in the tumor at diagnosis was already present several years before the diagnosis of FL. 8,9 Many aspects regarding the fate and site(s) of these FL-like B cells remain open, particularly those regarding their role as precursors of FL.…”

Section: Introductionmentioning

confidence: 99%

Early lesions of follicular lymphoma: a genetic perspective

Mamessier¹,

Song

Éberlé

et al. 2013

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nposed to distinguish FLIS from partial involvement by FL (PFL). In PFL there is greater architectural distortion, and the diagnosis of lymphoma is more evident histologically. However, interestingly, patients with PFL appear to present with low-stage disease, with a relatively low risk of progression and often a very prolonged disease-free interval with limited therapy. 12 Thus, PFL may represent a bona fide early stage in the biological evolution of FL, and not just a limited state of lymph node replacement by a fully developed neoplasm.14 Advances in laser capture microdissection now enable the isolation of even small numbers of cells representative of the clonotypic population, 15 and improvements in genomic methods allow the analysis of genetic aberrations in DNA derived from formalin-fixed, paraffin-embedded tissues. These new technologies now provide the unique opportunity to explore the genetic landscape of these early lesions, and to understand their relationship to overt FL better. Methods SamplesMost cases were selected from formalin-fixed, paraffin-embedded archive specimens submitted to the Hematopathology Section at the National Cancer Institute (NCI) or the Institute of Pathology, at the Medical University of Vienna. Seven cases of FLIS, five cases of PFL and five cases of DFL were identified based on previously published criteria. 11,12 Patients with FLIS and PFL had no other evidence of disease during the period of follow-up. 12 These samples were compared to five cases of FL grade 1-2 and five of FL grade 3A, included as controls of the most frequent alterations occurring in FL. Finally, sections of reactive follicular hyperplasia (RFH, n=2) and laser micro-dissected lymphoid cells from uninvolved areas of FLIS#3 (FLIS background) were also hybridized and used as references for normal cells (Online Supplementary Table S1). Only cases with confirmed t(14;18) were included in the study. The Institutional Review Boards of the NCI and the Medical University of Vienna approved the study. Laser capture microdissection, DNA extraction and quality controlTo obtain sufficient enrichment of lesional cells positive for t(14;18), which was necessary for the genome-wide array analysis, BCL2 + GC were microdissected from the selected FLIS/PFL/DFL/FL grade 1-2 cases. Laser capture microdissection was performed using a Leica LMD6000 (Leica Microsystems, Germany) on hematoxylin-stained slides with BCL2 + immunostained slides as a guide for involved follicles.15 BCL2-negative GC were microdissected from RFH, without evidence of FLIS. Tumor cell DNA was isolated from FL grade 3A without microdissection, given the high tumor cell content (>75%). DNA was extracted using a QIAamp ® DNA FFPE Kit. The amount of DNA collected from the different cases ranged from 506 to 2820 ng. With a calculation of 6.6 pg of DNA/cell this amounts to a minimum of 77,000 cells per case needed for appropriate hybridization. The integrity of the DNA was controlled with an Agilent DNA1...

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“…Such oncogenic events could already be detected in early FL lesions including FL in situ (FLIS). 6,7 The frequency of t(14;18) pos circulating B cells increases with age and exposure to pesticides, [8][9][10][11] reflecting the persistence and expansion of clonal populations of memory B cells bearing genotypic and phenotypic features of FL cells and called FL-like cells (FLLCs). Existence of t(14;18) pos precursor lymphoma-initiating cells has been recently supported by 2 reports of clonally related FL arising in both the donor and the recipient after allogeneic hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%