Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis

Roulland, Sandrine; Navarro, Jean Marc; Grenot, Pierre; Milili, Michèle; Agopian, Julie; Montpellier, Bertrand; Gauduchon, Pascal; Lebailly, Pierre; Schiff, Claudine; Nadel, Bertrand

doi:10.1084/jem.20061292

Cited by 183 publications

(113 citation statements)

References 30 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…70,72 This situation may represent tissue infiltration of circulating antigen-experienced, clonal expansions of B cells carrying the t(14;18) translocation commonly detected in healthy persons, termed FL-like B cells. 77 These circulating t(14;18)-positive clones, which are more prevalent among persons with pesticide exposure, appear to lack additional oncogenic events to develop into an overt lymphoma. It is interesting that some persons may carry several different clones with the t(14;18), although usually one of them largely predominates over the others, suggesting that these clones may arise in a context that facilitates the translocation and subsequent expansion.…”

Section: Early Lesions In Lymphoid Neoplasmsmentioning

confidence: 99%

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

Campo

Swerdlow

Harris

et al. 2011

Blood

1,782

1,414

View full text Add to dashboard Cite

The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field. (Blood. 2011

show abstract

Section: Early Lesions In Lymphoid Neoplasmsmentioning

confidence: 99%

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

Campo

Swerdlow

Harris

et al. 2011

Blood

1,782

1,414

View full text Add to dashboard Cite

show abstract

“…The genetic hallmark of FL, t(14;18)(q32;q21), which places the B-cell leukemia/lymphoma 2 (BCL2) oncogene under control of the Ig heavy-chain enhancer, is found in 80-90% of tumors (6). However, this event is also frequently found in rare cells in healthy individuals, the majority of whom do not go on to develop FL (7,8). This and other evidence therefore suggests that BCL2 translocations are not sufficient for lymphomagenesis and may be harbored in FL precursors, and that secondary genetic alterations are needed to drive clinical disease (4, 9, 10).…”

mentioning

confidence: 99%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

325

372

View full text Add to dashboard Cite

Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. lymphoma | exome | hierarchy | antigen presentation | CREBBP

show abstract

“…2 Almost all cases of FL harbor the t(14;18)(q32;q21) chromosomal translocation, resulting in overexpression of the oncogene BCL2. The frequent occurrence of the t(14;18)(q32;q21) translocation in B cells in the peripheral blood of healthy individuals 3 as well as the occurrence of "FL in situ" with a low risk of progression demonstrate that the translocation alone is insufficient for a malignant phenotype. 4,5 Specific attention has been focused on the microenvironment, especially of germinal centers of lymph nodes (LN).…”

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

View full text Add to dashboard Cite

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...

show abstract

Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis

Cited by 183 publications

References 30 publications

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

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

Contact Info

Product

Resources

About