Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Sutton, Lesley Ann; Minga, Eva; Agathangelidis, Andreas; Nichelatti, Michele; Tsanousa, Athina; Scarfò, Lydia; Davis, Zadie; Yan, Xinfeng; Shanafelt, Tait D.; Plevová, Karla; Sandberg, Yorick; Vojdeman, Fie Juhl; Boudjogra, Myriam; Τζένου, Τατιάνα; Chatzouli, Maria; Chu, Charles C.; Veronese, Silvio; Gardiner, Anne; Mansouri, Larry; Smedby, Karin E.; Pedersen, Lone Bredo; Lom, Kirsten van; Giudicelli, Véronique; Francová, Hana; Nguyen‐Khac, Florence; Panagiotidis, Panagiotis; Juliusson, Gunnar; Angelis, Lefteris; Anagnostopoulos, Achilles; Lefranc, Marie Paule; Facco, Monica; Trentin, Livio; Catherwood, Mark; Montillo, Marco; Geisler, Christian H.; Langerak, Anton W.; Pospı́šilová, Šárka; Chiorazzi, Nicholas; Oscier, David; Jelinek, Diane F.; Darzentas, Nikos; Belessi, Chrysoula; Davi, Frédéric; Rosenquist, Richard; Ghia, Paolo; Stamatopoulos, Kostas

doi:10.1016/s2352-3026(14)00005-2

Cited by 101 publications

(110 citation statements)

References 34 publications

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“…40 Finally, we looked to subset #4, the largest subset within M-CLL and now considered as a prototype for indolent disease. 14,23 Previous studies have reported that subset #4 is virtually devoid of cytogenetic aberrations associated with adverse prognosis [del(11q) and, especially, del(17p)]. 16 Herein, we not only confirm and significantly extend these observations, but also take a decisive step further by showing that subset #4 essentially lacks recurrent gene mutations, at least amongst the five genes analyzed.…”

Section: A C Bsupporting

confidence: 83%

“…23 A similarly skewed distribution of genomic aberrations was identified for another very aggressive CLL subset, subset #2, which is the largest subset overall.…”

Section: Discussionmentioning

confidence: 76%

“…10,[15][16][17][18][19][20][21][22][23][24][25] In addition, preliminary observations in CLL, in relatively small patient series, suggest that the frequency and patterns of mutations within several genes, namely, NOTCH1, SF3B1 and TP53, may differ amongst subsets of patients carrying stereotyped BcRs, the paradigmatic example being the recently observed enrichment of SF3B1 mutations in the clinically aggressive subset #2. [26][27][28] With this in mind, we sought to systematically evaluate the mutational status of BIRC3, MYD88, NOTCH1, SF3B1 and TP53 in 565 CLL patients assigned to one of 10 major stereotyped subsets, and representing cases with varying SHM status, i.e.…”

Section: Different Spectra Of Recurrent Gene Mutations In Subsets Of mentioning

confidence: 99%

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Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

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Section: A C Bsupporting

confidence: 83%

“…23 A similarly skewed distribution of genomic aberrations was identified for another very aggressive CLL subset, subset #2, which is the largest subset overall.…”

Section: Discussionmentioning

confidence: 76%

Section: Different Spectra Of Recurrent Gene Mutations In Subsets Of mentioning

confidence: 99%

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Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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“…For example, stereotyped subsets #1, #2, #6 and #8 often present as more aggressive CLL. 6 Furthermore, independent studies demonstrated frequent associations between specific genetic aberrations in CLL patients and stereotyped subsets.…”

Section: A B C D E F Gmentioning

confidence: 99%

“…11 In contrast, subset #4 patients are characterized by relatively young age at diagnosis, an indolent disease course, and a rare need for therapy. 6 The mechanisms that trigger BCR activation in CLL have not been fully elucidated, although BCR activation in the lymphoid tissues by autoantigens and microbial antigens is the most plausible mechanism, together with homotypic interaction of BCR-binding epitopes within the heavy and light chain of selected stereotyped BCRs.…”

Section: A B C D E F Gmentioning

confidence: 99%

Calreticulin as a novel B-cell receptor antigen in chronic lymphocytic leukemia

et al. 2017

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Molecular Genetics of Chronic Lymphocytic Leukaemia

Makewita

Strefford

2019

Encyclopedia of Life Sciences

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Chronic lymphocytic leukaemia (CLL) is a B‐cell malignancy and the most prevalent leukaemia in the Western world, most prevalent in elderly individuals. The disease exhibits vast clinical heterogeneity, ranging from a benign disease for many decades, to one requiring immediate treatment. With the application of modern genomic technologies, we now have a detailed view of the genomic architecture of the CLL genome. This includes a detailed catalogue of the genes targeted by copy number changes and mutations in the disease, as well as their clinical impact. In addition, we have an expanding understanding of the epigenetic profile of the disease that gives fundamental insights into the original transforming cell, and the regulatory networks contributing to the disease. This information has considerable clinical implications, improving diagnosis, prognostication and helping to guide therapeutic interventions with greater accuracy. Key Concepts CLL is a disease with a very heterogeneous clinical outcome such that patients can exhibit an indolent or a progressive disease resistant to chemo‐immunotherapy. This reflects considerable biological variability such that the mutational and epigenomic landscape differs between patients. Only by understanding this biological variability can a patient's clinical heterogeneity be understood. Immunogenetic analysis, through the study of immunoglobulin structure, has helped divide CLL patients into two prognostically relevant subgroups. Chromosomal deletions and aneuploidy events, not fusion‐genes and chromosomal rearrangements define CLL, where their presence can aid in patient stratification. The genome of CLL harbours a relatively low number of somatic lesions, but those that are identified target genes important in DNA damage response, cell cycle control, intracellular signalling, RNA processing and chromatin remodelling. Epigenetic analysis of CLL provides important information regarding the cell from which the tumour arose, and also the regulatory mechanisms that are dysregulated.

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Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Cited by 101 publications

References 34 publications

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Calreticulin as a novel B-cell receptor antigen in chronic lymphocytic leukemia

Molecular Genetics of Chronic Lymphocytic Leukaemia

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