Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen

Sutton, Lesley-Ann; Kostareli, Efterpi; Hadzidimitriou, Anastasia; Darzentas, Nikos; Tsaftaris, Athanasios; Anagnostopoulos, Achilles; Rosenquist, Richard; Stamatopoulos, Kostas

doi:10.1182/blood-2009-05-221309

Cited by 68 publications

(80 citation statements)

References 62 publications

(99 reference statements)

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“…37,38 However, no such bias is evident in other B-cell lymphomas, for example, CLL or MCL, where among the rearrangements using the IGHV1-2 gene, alleles *02 and *04 are detected at roughly similar frequencies. 8,24 This restricted usage of allele *04 in SMZL is noteworthy, given that it differs from allele *02 by a single amino acid, and can be considered as a molecular argument for selection.…”

Section: Discussionmentioning

confidence: 99%

“…14 In order to evaluate the presence of intraclonal diversification, subcloning analysis of the IGHV --IGHD --IGHJ PCR amplicons from four cases expressing IGHV1-2*04 IG receptors was performed, as described previously. 24 Sequence analysis and interpretation PCR amplicons were subjected to direct sequencing on both strands. Overall, 345 productive IGHV --IGHD --IGHJ rearrangements were evaluated (eight cases carried double productive rearrangements): of these, 160 have been reported in previous publications by our groups (Supplementary information).…”

Section: Pcr Amplification Of Ighv --Ighd --Ighj Rearrangementsmentioning

confidence: 99%

“…Furthermore, interpretation of results for all cases was performed de novo in the context of this study, following the approaches reported in our recent publications. 8,24,28 Molecular modeling In order to explore the possible modifications in the antibody structure caused by a single amino-acid replacement---namely, the arginine (R)-totryptophan (W) substitution at position VH FR3-75 to obtain an IGHV1-2*04-rearranging antibody---we performed a molecular dynamics study of the human anti-polyhydroxybutyrate antibody F v : IGHV1-2*02 IGKV1-39*01/1D-39*01 (Protein Data Bank code 2D7T). Replacement of the VH FR3-75 R (germline for IGHV1-2*02) by the W residue (germline for IGHV1-2*04) was executed by the COOT algorithm.…”

Section: Pcr Amplification Of Ighv --Ighd --Ighj Rearrangementsmentioning

confidence: 99%

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Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

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Section: Discussionmentioning

confidence: 99%

Section: Pcr Amplification Of Ighv --Ighd --Ighj Rearrangementsmentioning

confidence: 99%

Section: Pcr Amplification Of Ighv --Ighd --Ighj Rearrangementsmentioning

confidence: 99%

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Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

et al. 2012

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“…We recently investigated intraclonal diversification (ID) within the IG genes of patients with CLL and found that most cases showed no or low levels of ID. In sharp contrast, we reported intense ID within both the heavy and light chain IG genes of patients assigned to subset #4 (29,30).…”

Section: Sutton Et Al Over Time Intraclonal Dynamics Of Cll Subset #4mentioning

confidence: 50%

“…All amplification reactions were run using the high-fidelity Accuprime Pfx polymerase (Invitrogen) and purified PCR amplicons were subjected to direct sequencing on both strands (16,17,(29)(30)(31). …”

Section: Pcr Amplification Of Ig Rearrangementsmentioning

confidence: 99%

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

Sutton

Kostareli²,

Stalika

et al. 2013

Mol Med

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Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Though highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of 8 subset #4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially, however at later time-points the minor cluster had often disappeared and hence been selected against. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset #4.

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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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Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen

Cited by 68 publications

References 62 publications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

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

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