Clonal selection in the bone marrow involvement of follicular lymphoma

Bognár, Á; Csernus, Balázs; Bödör, Csaba; Reiniger, Lilla; Szepesi, Ágota; Tóth, Erika; Kopper, László; Matolcsy, András

doi:10.1038/sj.leu.2403844

Cited by 35 publications

(40 citation statements)

References 33 publications

(41 reference statements)

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“…Dissemination of FL clones among different lymph follicles and LN has been documented. [16][17][18][19]21,30 Studies showing that FL cells colonize non-neoplastic germinal centers and that non-neoplastic germinal centers can serve as a niche for FL cells are further supported by the concept of "in situ" FL, which represents infiltration of pre-existing non-neoplastic germinal centers by FL cells, rather than de novo formation of malignant germinal centers. 17,[31][32][33] Our conclusion that FL originates in the LN is consistent with the hypothesis of a possible dormant FL tumor stem cell harboring an unmutated, rearranged IgV H/L gene as part of the t(14;18)(q32;q21) translocation, which is possibly exposed to the somatic hypermutation machinery by passing the germinal centers of LN, acquiring additional point mutations and progressing to clinically overt FL.…”

Section: Discussionmentioning

confidence: 83%

“…6,10 Bognar et al indicated that the BM niche plays a decisive role in FL, suggesting early infiltration events from the LN compartment. 21 Applying the commonly used CLUSTALembedded multiple sequence alignment (MSA) algorithm, however, they were unable to delineate migration directions in relation to time. 36,37 A basic feature of MSA algorithms is to calculate the evolutionary distance of operational taxonomic units (OTU), for instance of the genetic distance of nucleotide sequences, by a pairwise comparison of all units.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 However, the molecular details of tumor cell dissemination into the BM are largely unknown. 21,22 We conducted a simultaneous mutational analysis of the IgV H genes of LN and corresponding BM specimens from three patients with FL, to delineate the migration of FL cells between these two compartments on the basis of reconstructed temporal sequences of FL cell clones. We used a newly ©2013 Ferrata Storti Foundation.…”

Section: Introductionmentioning

confidence: 99%

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Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

et al. 2013

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ABSTRACTdeveloped algorithm to describe clonal hierarchy and migration patterns more thoroughly. Methods Patients, histology, and immunohistochemistryThis study comprised three patients with synchronous LN and BM infiltration by FL at presentation. Biopsies were performed during the diagnostic and staging procedures. The selection criteria were the diagnosis of FL according to the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.1 Clinical information was obtained from the patients' medical records. Material was collected from patients after their informed consent in accordance with the Declaration of Helsinki. The study was approved by the responsible institutional ethic boards. Further details are provided in the Online Supplementary Methods. Sequence analysis of IgV H genes and definition of mutational patternsDNA from the IgV H gene segments was extracted and amplified as described elsewhere. 23,24 Cloning, sequencing, and the mutational analysis of the obtained segments are described in detail in the Online Supplementary Methods. Delineation of tumor cell evolution by construction of pedigreesFor each patient and each compartment (LN and BM separately), the mutational patterns of IgV H gene segments were arranged in an ascending order of mutations to illustrate the mutational hierarchy of intraclonal sequence heterogeneity. Consequently, mutational patterns of early clones with few mutations had to be included in successor clones. When direct transition of one mutation pattern into that of successor clones with higher mutation loads was not observable, hypothetical predecessor clones (HPC) were introduced to retrace the evolution of sequenced clones back to the determined initial V H DJ H gene rearrangement (wild-type sequence). Accordingly, compartment-specific pedigrees were constructed. Thereafter, a third "summary-pedigree" comprising all sequenced clones was constructed, to evaluate the possibility of inter-compartmental exchange between LN and BM. Generation of hypothetical predecessor clones and delineation of migration probabilityFor each sequenced FL population (i.e. LN, BM, and LN and BM together) the pool of possible HPC was derived from mutations shared by at least two sequenced clones. To select the most appropriate predecessor clones from the abundance of generated HPC, the probability measurement was introduced (Figure 1). Only HPC with the highest probability measurement values were introduced until the evolution of sequenced clones could be retraced to the "wild-type sequence". Already established clone groups could not be disrupted by HPC with lower probability measurement values. These calculations resulted in a LN, a BM and an inter-compartment pedigree. If HPC of the inter-compartment pedigree displayed a higher probability measurement value than the corresponding LN or BM counterparts, inter-compartment migration was considered. The LN or BM allocation of these inter-compartment HPC was directed by the LN or BM affiliation of the majority of ev...

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

et al. 2013

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“…Thus, individual tumor cells can each have slightly different Ig variable region sequences. 5 Random mutations should eventually result in stop codons and loss of BCR protein expression. However, FL tumors maintain a surface BCR, indicating a selective force favoring retention of a functional BCR.…”

Section: Introductionmentioning

confidence: 99%

Self-antigen recognition by follicular lymphoma B-cell receptors

Sachen¹,

Strohman

Singletary³

et al. 2012

Blood

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IntroductionFollicular lymphoma (FL) is a slowly progressive and largely incurable human B-cell malignancy. Transformation to a more aggressive lymphoma, such as diffuse large B-cell lymphoma, is common and strongly associated with an increase in morbidity and mortality. A chromosomal translocation t(14:18) is the hallmark of this disease, and it is found in 85%-90% of cases. It results in the juxtaposition of the BCL2 proto-oncogene with the immunoglobulin (Ig) heavy chain gene, IGH, leading to deregulated overexpression of Bcl-2 protein, a major inhibitor of apoptosis. However, the t(14:18) translocation is insufficient to cause malignancy as it is detectable in rare B cells from healthy persons. 1-3 Thus, FL pathogenesis requires additional signals beyond that imparted by the deregulation of BCL2. The observation that FL cells isolated from patients fail to survive in vitro and undergo spontaneous apoptosis supports the hypothesis that extrinsic microenvironmental factors are required for maintenance and expansion of FL. 4 Phenotypically, FL tumor cells resemble antigen-experienced germinal center B cells. Their Ig genes, which are rearranged to produce a functional B-cell receptor (BCR), have numerous point mutations compared with their germline counterparts, and this process of somatic hypermutation (SHM) is ongoing as the malignant clone expands and diversifies. Thus, individual tumor cells can each have slightly different Ig variable region sequences. 5 Random mutations should eventually result in stop codons and loss of BCR protein expression. However, FL tumors maintain a surface BCR, indicating a selective force favoring retention of a functional BCR. Furthermore, therapy with anti-idiotype antibodies directed against the BCR did not select for the outgrowth of BCR-negative variants. Rather, this therapy selected for the outgrowth of cells that had amino acid substitutions in the targeted V region sequence, making them unrecognizable by the anti-idiotype antibody. 6 Other in vitro studies with malignant B-cell lines have shown that experimental knockdowns of the BCR and members of its signaling pathway result in growth arrest, implicating their importance in tumor cell survival. 7 The BCR can transmit a tonic survival signal, but this is greatly augmented on its binding to a cognate antigen. 8 There is indirect evidence to suggest that antigen recognition plays a role in the pathogenesis of FL. SHM can introduce silent or replacement mutations, the latter leading to an amino acid substitution. In a normal immune response, B cells with mutations resulting in higher binding affinity for the inciting antigen preferentially survive. This selective pressure leads to enrichment of replacement mutations in the complementarity determining regions (CDRs) of the BCR, and an under representation of replacement mutations in the framework regions (FWRs). 9 This same distribution of replacement and silent mutations has been reported for the BCRs of FL cells, 5 and the intraclonal diversity resulting from ongoing SHM...

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“…Indeed a bone marrow-specific niche has already been proposed by several groups. [18][19][20] In consequence it could even be that clonally related and bone marrow-resident FLLC, instead of fully malignant FL cells, cause a relapse of lymphoma ( Figure 1E). …”

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confidence: 99%

Origin and migration of follicular lymphoma cells

Kluin

2013

Haematologica

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F ollicular lymphoma (FL) was described for the first time by Brill and Symmers in 1925. The primary cytogenetic lesion, the t(14;18) was identified in 1982, and the breakpoint at BCL2 in 1985. Based on observations that the t(14;18) originates from an erroneous recombination event in precursor B cells, 1 a model evolved in which the tumor develops linearly from such a precursor cell ( Figure 1A). Other cytogenetic events frequently accompany the t(14;18), and various authors have attempted to distinguish different subgroups of FL with differences in biological behavior, risk of transformation to an aggressive lymphoma, prognosis and overall survival on the basis of these additional events.2,3 Apart from these cytogenetic abnormalities not further discussed here, it is evident that FL represents a germinal center lymphoma with high expression of activation-induced deaminase (AID) and in consequence a pattern of ongoing somatic hypermutations of immunoglobulin (IG) loci. 4,5 This is not necessarily a continuous process since tumor cells may leave and (re)enter a germinal center and, in consequence, may periodically acquire novel somatic hypermutations of the IG genes. Indeed, by analysis of individual tumor cells or by molecular cloning of IGH rearrangements from a pool of tumor cells, it became evident that within each individual lymphoma not all tumor cells share the same somatic hypermutations. This implies subclonal evolution of the lymphoma, each clone being detectable by a unique fingerprint. Thus sampling of multiple (subsequent) lymph nodes of a FL patient might show different fingerprints of these mutations and this type of analysis may provide us with a "genealogical tree" of the individual lymphoma ( Figure 1B).The prototypic FL is a histologically low grade (grade 1 or 2) and clinically indolent lymphoma and affected patients have a median overall survival of approximately 7 years or longer. Of note the great majority of patients present with disseminated disease at the time of diagnosis implying an equally long or even longer period of subclinical disease. This is in line with the observations that approximately half of all healthy adult individuals harbor one or more B-cell clones with a t(14;18), only very few of these clones developing into clinically relevant disease. At present these cells are called "follicular lymphoma-like cells" or FLLC. [6][7][8] In fact occasional cells carrying these t(14;18) can already be identified in hyperplastic tonsils from children.9 Besides, so-called follicular lymphoma in situ (FLIS) lesions can be identified in less than 3% of all reactive lymph nodes. 10 In these lymph nodes, some germinal centers are focally involved by FL cells as detected by immunohistochemistry, polymerase chain reaction analysis and in situ hybridization for the t(14;18).Interestingly and in contrast to what was expected, these FLLC and likely also FLIS lesions represent expansions of lowaffinity IgM(D) expressing (post-germinal) memory B cells that have accumulated high loads of somatic ...

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Clonal selection in the bone marrow involvement of follicular lymphoma

Cited by 35 publications

References 33 publications

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

Self-antigen recognition by follicular lymphoma B-cell receptors

Origin and migration of follicular lymphoma cells

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