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Stamatopoulos, Kostas
Publications (10 of 12) 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, 282-291 p.Article, 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, 5292-5301 p.Article 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, 77-83 p.Article 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, 2926-2933 p.Article 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, 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
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, 1547-1554 p.Article 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
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, 968-971 p.Article 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, E334-E340 p.Article 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
Pouliou, E., Xochelli, A., Kanellis, G., Stalika, E., Sutton, L.-A., Navarro, A., . . . Papadaki, T. (2017). Numerous Ontogenetic Roads to Mantle Cell Lymphoma: Immunogenetic and Immunohistochemical Evidence. American Journal of Pathology, 187(7), 1454-1458.
Open this publication in new window or tab >>Numerous Ontogenetic Roads to Mantle Cell Lymphoma: Immunogenetic and Immunohistochemical Evidence
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2017 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 7, 1454-1458 p.Article in journal (Refereed) Published
Abstract [en]

To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal (n = 151), extranodal. (n = 28), and primary splenic (n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimalto pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases (P < 0.001) and used the IGHV1-8 gene more frequently (P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-328974 (URN)10.1016/j.ajpath.2017.02.017 (DOI)000404320500003 ()28457696 (PubMedID)
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2017-09-12Bibliographically approved
Vardi, A., Vlachonikola, E., Karypidou, M., Stalika, E., Bikos, V., Gemenetzi, K., . . . Hadzidimitriou, A. (2017). Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements. Leukemia, 31(7), 1555-1561.
Open this publication in new window or tab >>Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, 1555-1561 p.Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-330040 (URN)10.1038/leu.2016.362 (DOI)000404745300010 ()
Funder
EU, Horizon 2020, 692298
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2017-09-28Bibliographically approved
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