Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone

Carlotti, Emanuela; Wrench, David; Matthews, Janet; Iqbal, Sameena; Davies, Andrew; Norton, A. J.; Hart, Janace; Lai, Raymond; Montoto, Silvia; Gribben, John G.; Lister, T. Andrew; Fitzgibbon, Jude

doi:10.1182/blood-2008-08-174839

Cited by 127 publications

(107 citation statements)

References 24 publications

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“…7 An alternative scenario, however, might be the divergent evolution of both the indolent and the aggressive phase from a common precursor cell. 7,8 In RS, the precise timing of onset of the RS clone during CLL history is unknown. Also, although antigen stimulation may be important for the growth of indolent B-cell malignancies, it might no longer be required by the subsequent aggressive malignancy.…”

Section: 6mentioning

confidence: 99%

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Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Rossi¹,

Spina²,

Forconi³

et al. 2011

Intl Journal of Cancer

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Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 3 10 23 vs. 0.13 3 10 -3 ; p 50.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.The definition of Richter syndrome (RS) encompasses two biologically different conditions: (i) transformation of chronic lymphocytic leukemia (CLL) to clonally related diffuse large B-cell lymphoma (DLBCL) and (ii) development of a DLBCL unrelated to the CLL clone. [1][2][3][4] The role of antigen in promoting CLL transformation to RS is supported by the recent observation of a high prevalence of stereotyped B-cell receptors in CLL transforming to RS, and by the documentation of biased usage of immunoglobulin heavy variable (IGHV) genes, including IGHV4-39. 5,6A common assumption in the context of transformation from indolent to aggressive B-cell malignancy holds that transformation reflects the final stage of evolution of the indolent B-cell clone.7 An alternative scenario, however, might be the divergent evolution of both the indolent and the aggressive phase from a common precursor cell. 7,8 In RS, the precise timing of onset of the RS clone during CLL history is unknown. Also, although antigen stimulation may be important for the growth of indolent B-cell malignancies, it might no longer be required by the subsequent aggressive malignancy.9 With respect to RS, antigen stimulation contributes to CLL predisposition to DLBCL, 6 but it is unclear whether antigen retains any role once that transformation has occurred.

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Section: 6mentioning

confidence: 99%

“…7,8 In RS, the precise timing of onset of the RS clone during CLL history is unknown. Also, although antigen stimulation may be important for the growth of indolent B-cell malignancies, it might no longer be required by the subsequent aggressive malignancy.…”

Section: 6mentioning

confidence: 99%

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Rossi¹,

Spina²,

Forconi³

et al. 2011

Intl Journal of Cancer

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“…4,5 Specific attention has been focused on the microenvironment, especially of germinal centers of lymph nodes (LN). [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.…”

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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“…The role of these FL-like cells in the pathogenesis of FL remains elusive. Nonetheless, precursor lymphoma-initiating cells must exist, as illustrated by two reports of FL arising in both the donor and the recipient after allogeneic hematopoietic stem cell transplantation (32,33). In the most recent of these studies, the t(14;18) was retrospectively detected in the donor lymphocyte infusion, together with a low abundance of mutated alleles matching 14 of the 15 gene mutations that were shared between the tumors from the donor and the recipient (33).…”

Section: Cell Of Originmentioning

confidence: 99%

“…TFL shares a distinct gene expression profile and immunophenotype with the original FL (97). Similar to progression of FL, the process of transformation may occur by either direct clonal evolution or emergence from an ancestral clone that arises from a supposed common progenitor (32).…”

Section: Complex Pathways Of Progression and Transformationmentioning

confidence: 99%

Pathogenesis of follicular lymphoma

Kridel¹,

Sehn²,

Gascoyne³

2012

J. Clin. Invest.

279

207

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The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.

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Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone

Cited by 127 publications

References 24 publications

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

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

Pathogenesis of follicular lymphoma

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