Molecular pathways in follicular lymphoma

Bende, Richard J.; Smit, Laura A.; Noesel, C. J. M. van

doi:10.1038/sj.leu.2404426

Cited by 118 publications

(106 citation statements)

References 151 publications

(172 reference statements)

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“…[6][7][8] As the putative malignant counterpart of germinal center B cells, the (pre)-malignant FL cells are believed to overcome selective control mechanisms of the germinal center microenvironment by constitutive expression of the antiapoptotic protein Bcl-2, allowing for secondary genetic aberrations leading to a fully malignant phenotype and progression of FL. [9][10][11][12] The germinal center B-cell origin of FL is supported by ongoing somatic hypermutation of immunoglobulin heavy chain variable region (IgV H )-genes of t(14;18)-positive FL cells. 13 The mutation patterns in the IgV H genes of FL have been found to be very similar to those in normal antigenselected B cells.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…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.…”

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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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“…Follicular lymphoma frequently involves the spleen secondarily and splenectomy may occasionally be the procedure leading to its initial diagnosis [23][24][25]. Two patterns of involvement have been identified, which occur with similar frequency (Fig.…”

Section: Follicular Lymphomamentioning

confidence: 99%