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Stamatopoulos, Kostas
Publications (10 of 14) Show all publications
Stamatopoulos, K., Agathangelidis, A., Rosenquist, R. & Ghia, P. (2017). Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia, 31(2), 282-291
Open this publication in new window or tab >>Antigen receptor stereotypy in chronic lymphocytic leukemia
2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 2, p. 282-291Article, review/survey (Refereed) Published
Abstract [en]

The discovery of almost identical or 'stereotyped' B-cell receptor immunoglobulins (BcR IG) among unrelated patients with chronic lymphocytic leukemia (CLL) cemented the idea of antigen selection in disease ontogeny and evolution. The systematic analysis of the stereotypy phenomenon in CLL revealed that around one-third of CLL patients may be grouped into subsets based on shared sequence motifs within the variable heavy complementarity determining region 3. Stereotyped subsets display a strikingly similar biology of the leukemic clones, referring to many different levels, from the immunogenetic and genetic and extending to the epigenetic and functional levels. Even more importantly, the homogeneity of stereotyped subsets has clinical consequences as patients assigned to the same stereotyped subset generally exhibit an overall similar disease course and outcome. In other words, stereotypy-based patient classification of CLL has already provided a more compartmentalized view of this otherwise heterogeneous disease and can assist in refining prognostication models. While this is relevant only for the one-third of cases expressing stereotyped BcR IG; in principle, however, the findings from further analysis of the stereotyped subsets may also contribute towards improved understanding of the remaining non-stereotyped fraction of CLL patients.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-320092 (URN)10.1038/leu.2016.322 (DOI)000394058800003 ()27811850 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2017-04-27Bibliographically approved
Xochelli, A., Baliakas, P., Kavakiotis, I., Agathangelidis, A., Sutton, L. A., Minga, E., . . . Stamatopoulos, K. (2017). Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes. Clinical Cancer Research, 23(17), 5292-5301
Open this publication in new window or tab >>Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 17, p. 5292-5301Article in journal (Refereed) Published
Abstract [en]

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.  

Keyword
B-cell receptors, gene mutational status, antigen receptors, CD38 expression, genomic aberrations, sequence-analysis, I-antigen, immunoglobulin, antibodies, dna
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-334402 (URN)10.1158/1078-0432.CCR-16-3100 (DOI)000409037300034 ()28536306 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-11Bibliographically approved
Xochelli, A., Oscier, D. & Stamatopoulos, K. (2017). Clonal B-cell lymphocytosis of marginal zone origin. Baillière's Best Practice & Research: Clinical Haematology, 30(1-2), 77-83
Open this publication in new window or tab >>Clonal B-cell lymphocytosis of marginal zone origin
2017 (English)In: Baillière's Best Practice & Research: Clinical Haematology, ISSN 1521-6926, E-ISSN 1532-1924, Vol. 30, no 1-2, p. 77-83Article in journal (Refereed) Published
Abstract [en]

Monoclonal B cell Lymphocytosis (MBL) is the term used to characterize individuals presenting with lymphocytosis in the absence of lymphadenopathy, organomegaly or any other features suggestive of an active disease. Based on the immunophenotypic findings, MBL cases are sub-categorized into chronic lymphocytic leukemia (CLL)-like, atypical CLL and non-CLL MBL. The latter corresponds to cases with immunophenotypic features suggestive of post germinal center derivation and still represents a diagnostic conundrum. Recent studies are starting to shed light on the true biological nature and clinical significance of this entity and have led to the introduction of the novel term clonal B lymphocytosis of marginal-zone origin (CBL-MZ); as well as the acknowledgement of CBL-MZ in the latest (2016) update of the WHO classification for lymphoid malignancies. Here we provide an overview of relevant research concerning non-CLL MBL and discuss clinicobiological implications and considerations.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2017
Keyword
CD5(-) lymphocytosis, Monoclonal B cell lymphocytosis, Marginal zone
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-320832 (URN)10.1016/j.beha.2016.08.028 (DOI)000397692700010 ()28288720 (PubMedID)
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-04-26Bibliographically approved
Mastrodemou, S., Stalika, E., Vardi, A., Gemenetzi, K., Spanoudakis, M., Karypidou, M., . . . Stamatopoulos, K. (2017). Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors. Leukemia and Lymphoma, 58(12), 2926-2933
Open this publication in new window or tab >>Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors
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2017 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 12, p. 2926-2933Article in journal (Refereed) Published
Abstract [en]

Chronic idiopathic neutropenia (CIN) is an acquired disorder of granulopoiesis characterized by female predominance and mostly uncomplicated course. Crucial to CIN pathophysiology is the presence of activated T lymphocytes with myelosuppressive properties in both peripheral blood (PB) and bone marrow (BM). We systematically profiled the T cell receptor beta chain (TRB) gene repertoire in CD8(+) cells of 34 CIN patients through subcloning/Sanger sequencing analysis of TRBV-TRBD-TRBJ gene rearrangements. Remarkable repertoire skewing and oligoclonality were observed, along with shared clonotypes between different patients, alluding to antigen selection. Cross-comparison of our sequence dataset with public TRB sequence databases revealed that CIN may rarely share common immunogenetic features with other entities, however, the CIN TRB repertoire is largely disease-biased. Overall, these findings suggest that CIN may be driven by long-term exposure to a restricted set of specific CIN-associated antigens.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keyword
Chronic idiopathic neutropenia, T cell receptor, antigen selection
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333418 (URN)10.1080/10428194.2017.1324154 (DOI)000406290000018 ()28535087 (PubMedID)
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2017-11-16Bibliographically approved
Minici, C., Gounari, M., Uebelhart, R., Scarfo, L., Duhren-von Minden, M., Schneider, D., . . . Degano, M. (2017). Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nature Communications, 8, Article ID 15746.
Open this publication in new window or tab >>Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15746Article in journal (Refereed) Published
Abstract [en]

Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR-BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-326495 (URN)10.1038/ncomms15746 (DOI)000402964200001 ()28598442 (PubMedID)
Funder
NIH (National Institute of Health), RO1 CA081554German Research Foundation (DFG), SFB1074EU, European Research Council, 694992
Available from: 2017-08-17 Created: 2017-08-17 Last updated: 2018-01-13Bibliographically approved
Ghia, P., Nadel, B., Sander, B., Stamatopoulos, K. & Stevenson, F. K. (2017). Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment. Paper presented at Symposium on Targeted Therapy in B-Cell Malignancies, SEP 29-30, 2016, Karolinska Inst, Stockholm, SWEDEN. Journal of Internal Medicine, 282(5), 395-414
Open this publication in new window or tab >>Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment
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2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 5, p. 395-414Article in journal (Refereed) Published
Abstract [en]

In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.

Keyword
chronic lymphocytic leukaemia, follicular lymphoma, lymphomagenesis, mantle cell lymphoma, microenvironment, splenic marginal zone lymphoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-339736 (URN)10.1111/joim.12608 (DOI)000413307000004 ()28393412 (PubMedID)
Conference
Symposium on Targeted Therapy in B-Cell Malignancies, SEP 29-30, 2016, Karolinska Inst, Stockholm, SWEDEN
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved
Young, E., Noerenberg, D., Mansouri, L., Ljungström, V., Frick, M., Sutton, L. A., . . . Damm, F. (2017). EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31(7), 1547-1554
Open this publication in new window or tab >>EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed) Published
Abstract [en]

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-314928 (URN)10.1038/leu.2016.359 (DOI)000404745300009 ()27890934 (PubMedID)
Note

E.Y. and D.N. contributed equally to this study as joint first authors.

R.R. and F.D. contributed equally as joint senior authors.

Available from: 2017-02-07 Created: 2017-02-07 Last updated: 2017-09-28Bibliographically approved
Rosenquist, R., Ghia, P., Hadzidimitriou, A., Sutton, L. A., Agathangelidis, A., Baliakas, P., . . . Stamatopoulos, K. (2017). Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia, 31(7), 1477-1481
Open this publication in new window or tab >>Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1477-1481Article in journal, Editorial material (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-335814 (URN)10.1038/leu.2017.125 (DOI)000404745300001 ()28439111 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-01-22Bibliographically approved
Sutton, L. A., Hadzidimitriou, A., Baliakas, P., Agathangelidis, A., Langerak, A. W., Stilgenbauer, S., . . . Stamatopoulos, K. (2017). Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification. Haematologica, 102(6), 968-971
Open this publication in new window or tab >>Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no 6, p. 968-971Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-332747 (URN)10.3324/haematol.2017.165605 (DOI)000402797300009 ()28566340 (PubMedID)
Funder
EU, Horizon 2020Swedish Cancer SocietySwedish Research Council
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2017-12-07Bibliographically approved
Rawstron, A. C., Ssemaganda, A., de Tute, R., Doughty, C., Newton, D., Vardi, A., . . . Newton, R. (2017). Monoclonal B-cell lymphocytosis in a hospital-based UK population and a rural Ugandan population: a cross-sectional study. The Lancet Global Health, 4(7), E334-E340
Open this publication in new window or tab >>Monoclonal B-cell lymphocytosis in a hospital-based UK population and a rural Ugandan population: a cross-sectional study
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2017 (English)In: The Lancet Global Health, ISSN 2352-3026, E-ISSN 2214-109X, Vol. 4, no 7, p. E334-E340Article in journal (Refereed) Published
Abstract [en]

Background Reported incidence of B-cell malignancies shows substantial geographical variation, being more common in the Americas and Europe than in Africa. This variation might reflect differences in diagnostic capability, inherited susceptibility, and infectious exposures. Monoclonal B-cell lymphocytosis (MBL) is a precursor lesion that can be screened for in apparently healthy people, allowing comparison of prevalence across different populations independently of health-care provision. We aimed to compare the prevalence and phenotypic characteristics of MBL in age-and-sex-matched populations from rural Uganda and the UK. Methods In this cross-sectional study, we recruited volunteers aged at least 45 years who were seronegative for HIV-1 from the established Ugandan General Population Cohort and obtained their whole-blood samples. We also obtained blood samples from anonymised waste material of age-and-sex-matched individuals (aged >45 years, with a normal blood count and no history of cancer) in the UK. We used flow cytometry to determine the presence of MBL, defined according to standard diagnostic criteria, in the samples and compared differences in the proportion of cases with chronic lymphocytic leukaemia (CLL)-phenotype MBL and CD5-negative MBL, as well as differences in absolute monoclonal B-cell count between the two cohorts. Findings Between Jan 15 and Dec 18, 2012, we obtained samples from 302 Ugandan volunteers and 302 UK individuals who were matched by age and sex to the Ugandan population. Overall MBL prevalence was higher in the Ugandan participants (42 [14%] individuals) than in the UK cohort (25 [8%]; p=0.038). CLL-phenotype MBL was detected in three (1%) Ugandan participants and 21 (7%) UK participants (p=0.00021); all three Ugandan participants had absolute monoclonal B-cell count below one cell per mu L, whereas the 21 UK participants had a median absolute number of circulating neoplastic cells of 4.6 (IQR 2-12) cells per mu L. The prevalence of CD5-negative MBL was higher in the Ugandan cohort (41 [14%], of whom two [5%] also had CLL-phenotype MBL) than in the UK cohort (six [2%], of whom two [33%] also had CLL-phenotype MBL; p<0.0001), but the median absolute B-cell count was similar (227 [IQR 152-345] cells per mu L in the Ugandan cohort vs 135 [105-177] cells per mu L in the UK cohort; p=0.13). Interpretation MBL is common in both Uganda and the UK, but the substantial phenotypic differences might reflect fundamental differences in the pathogenesis of B-cell lymphoproliferative disorders.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-330010 (URN)10.1016/S2352-3026(16)30192-2 (DOI)000405452300009 ()28668191 (PubMedID)
Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-11Bibliographically approved
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