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Stamatopoulos, Kostas
Publications (10 of 23) Show all publications
Baliakas, P., Jeromin, S., Iskas, M., Puiggros, A., Plevova, K., Nguyen-Khac, F., . . . Stamatopoulos, K. (2019). Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood, 133(11), 1205-1216
Open this publication in new window or tab >>Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact
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2019 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 133, no 11, p. 1205-1216Article in journal (Refereed) Published
Abstract [en]

Recent evidence suggests that complex karyotype (CK) defined by the presence of >= 3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with >= 5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and 112,119 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hyper-mutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with 112,119, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with >= 5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-381085 (URN)10.1182/blood-2018-09-873083 (DOI)000461508300007 ()30602617 (PubMedID)
Funder
EU, Horizon 2020EU, Horizon 2020Swedish Research Council
Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-04-23Bibliographically approved
Gounari, M., Ntoufa, S., Gerousi, M., Vilia, M. G., Moysiadis, T., Kotta, K., . . . Ghia, P. (2019). Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment [Letter to the editor]. Leukemia, 33(4), 1030-1034
Open this publication in new window or tab >>Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 4, p. 1030-1034Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-382772 (URN)10.1038/s41375-018-0335-2 (DOI)000463162400017 ()30607020 (PubMedID)
Funder
EU, Horizon 2020EU, Horizon 2020, 796491
Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-05-02Bibliographically approved
Moysiadis, T., Baliakas, P., Rossi, D., Catherwood, M., Strefford, J. C., Delgado, J., . . . Stamatopoulos, K. (2019). Different time-dependent changes of risk for evolution in chronic lymphocytic leukemia with mutated or unmutated antigen B cell receptors [Letter to the editor]. Leukemia, 33(7), 1801-1805
Open this publication in new window or tab >>Different time-dependent changes of risk for evolution in chronic lymphocytic leukemia with mutated or unmutated antigen B cell receptors
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 7, p. 1801-1805Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-390327 (URN)10.1038/s41375-018-0322-7 (DOI)000473724900022 ()30679797 (PubMedID)
Funder
EU, Horizon 2020, 702714EU, Horizon 2020EU, Horizon 2020Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Cancer SocietyErik, Karin och Gösta Selanders Foundation
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Xochelli, A., Bikos, V., Polychronidou, E., Galigalidou, C., Agathangelidis, A., Charlotte, F., . . . Stamatopoulos, K. (2019). Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations. Journal of Pathology, 247(4), 416-421
Open this publication in new window or tab >>Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 4, p. 416-421Article in journal (Refereed) Published
Abstract [en]

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
marginal zone lymphoma, ontogeny, immunoglobulin gene, antigen
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-379880 (URN)10.1002/path.5209 (DOI)000460465000003 ()30484876 (PubMedID)
Funder
EU, Horizon 2020, 692298EU, Horizon 2020, LQ1601Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2020-01-03Bibliographically approved
Papakonstantinou, N., Ntoufa, S., Tsagiopoulou, M., Moysiadis, T., Bhoi, S., Malousi, A., . . . Stamatopoulos, K. (2019). Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. International Journal of Cancer, 144(11), 2695-2706
Open this publication in new window or tab >>Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 11, p. 2695-2706Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.

Keywords
CLL, stereotypy, DNA methylation, gene expression, TP63
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-384059 (URN)10.1002/ijc.31999 (DOI)000467099500009 ()30447004 (PubMedID)
Funder
EU, Horizon 2020, 644906Swedish Cancer SocietyKnut and Alice Wallenberg FoundationEU, Horizon 2020, 692298Swedish Research CouncilEU, Horizon 2020, 702714
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Agathangelidis, A., Sutton, L. A., Hadzidimitriou, A., Tresoldi, C., Langerak, A. W., Belessi, C., . . . Ghia, P. (2018). Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation. Journal of Visualized Experiments (141), Article ID e57787.
Open this publication in new window or tab >>Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
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2018 (English)In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 141, article id e57787Article in journal (Refereed) Published
Abstract [en]

During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.

Place, publisher, year, edition, pages
JOURNAL OF VISUALIZED EXPERIMENTS, 2018
Keywords
Cancer Research, Issue 141, Chronic lymphocytic leukemia (CLL), somatic hypermutation (SHM), immunoglobulin, immunoglobulin heavy variable (IGHV), complementarity determining region 3 (CDR3), International ImMunoGene Tics information system (IMGT)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-376902 (URN)10.3791/57787 (DOI)000456469400033 ()30531723 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, Horizon 2020Swedish Cancer Society
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-02-12Bibliographically approved
Baliakas, P., Mattsson, M., Hadzidimitriou, A., Minga, E., Agathangelidis, A., Sutton, L. A., . . . Stamatopoulos, K. (2018). No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy [Letter to the editor]. Haematologica, 103(4), E158-E161
Open this publication in new window or tab >>No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy
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2018 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 4, p. E158-E161Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2018
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356894 (URN)10.3324/haematol.2017.182634 (DOI)000428242100006 ()29269523 (PubMedID)
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved
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.  

Keywords
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
Keywords
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
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