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Rosenquist, Richard
Alternative names
Publications (10 of 225) Show all publications
Rawstron, A. C., Kreuzer, K.-A., Soosapilla, A., Spacek, M., Stehlikova, O., Gambell, P., . . . Montserrat, E. (2018). Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry. Part B, Clinical cytometry., 94(1), 121-128
Open this publication in new window or tab >>Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project
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2018 (English)In: Cytometry. Part B, Clinical cytometry., ISSN 1552-4949, E-ISSN 1552-4957, Vol. 94, no 1, p. 121-128Article in journal (Refereed) Published
Abstract [en]

The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as “required” or “recommended” for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate “required” markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5–20 in 82/150 (55%), and <5 cases per week in 45/150 (30%). The consensus for “required” diagnostic markers included: CD19, CD5, CD20, CD23, Kappa, and Lambda. “Recommended” markers potentially useful for differential diagnosis were: CD43, CD79b, CD81, CD200, CD10, and ROR1. Reproducible criteria for component reagents were assessed retrospectively in 14,643 cases from 13 different centers and showed >97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as “required” for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus “recommended” panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated.

Keyword
chronic lymphocytic leukemia, flow cytometry, diagnosis
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-346369 (URN)10.1002/cyto.b.21595 (DOI)000423805500012 ()29024461 (PubMedID)
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2018-03-09Bibliographically 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.  

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
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
Löf, L., Arngården, L., Olsson-Strömberg, U., Siart, B., Jansson, M., Dahlin, J. S., . . . Kamali-Moghaddam, M. (2017). Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia. Scientific Reports, 7, 1-9, Article ID 623.
Open this publication in new window or tab >>Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-9, article id 623Article in journal (Refereed) Published
Abstract [en]

Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-319726 (URN)10.1038/s41598-017-00755-y (DOI)000398162400034 ()28377570 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 294409Swedish Cancer SocietySwedish Research Council
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2017-05-15Bibliographically approved
Rosenquist, R., Bea, S., Du, M.-Q. -., Nadel, B. & Pan-Hammarstrom, Q. (2017). Genetic landscape and deregulated pathways in B-cell lymphoid malignancies. 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), 371-394
Open this publication in new window or tab >>Genetic landscape and deregulated pathways in B-cell lymphoid malignancies
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2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 5, p. 371-394Article in journal (Refereed) Published
Abstract [en]

With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B-cell receptor/NF-kappa B pathway, NOTCH signalling, JAK-STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B-cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy-resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group.

Keyword
B-cell lymphomas, deregulated pathways, genetic aberrations, next-generation sequencing, prognosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-339735 (URN)10.1111/joim.12633 (DOI)000413307000003 ()
Conference
Symposium on Targeted Therapy in B-Cell Malignancies, SEP 29-30, 2016, Karolinska Inst, Stockholm, SWEDEN
Funder
Swedish Cancer SocietySwedish Research CouncilThe Karolinska Institutet's Research FoundationSwedish Childhood Cancer Foundation
Note

R. Rosenquist and S. Beà contributed equally to this work.

Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved
Law, P. J., Berndt, S. I., Speedy, H. E., Camp, N. J., Sava, G. P., Skibola, C. F., . . . Slager, S. L. (2017). Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nature Communications, 8, Article ID 14175.
Open this publication in new window or tab >>Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14175Article in journal (Refereed) Published
Abstract [en]

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P = 5.04 X 10 (-) (13)), 1q42.13 (rs41271473, P = 1.06 X 10 (-) (10)), 4q24 (rs71597109, P = 1.37 X 10 (-) (10)), 4q35.1 (rs57214277, P = 3.69 X 10 (-) (8)), 6p21.31 (rs3800461, P = 1.97 X 10 (-) (8)), 11q23.2 (rs61904987, P = 2.64 X 10 (-) (11)), 18q21.1 (rs1036935, P = 3.27 X 10 (-) (8)), 19p13.3 (rs7254272, P = 4.67 X 10 (-) (8)) and 22q13.33 (rs140522, P = 2.70 X 10 (-) (9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-316933 (URN)10.1038/ncomms14175 (DOI)000393338200001 ()28165464 (PubMedID)
Funder
NIH (National Institute of Health), NO1-CO-12400 K08CA134919 CA167552 CA149445 CA098122 CA186107 CA87969 CA49449 HHSN261201000026CSwedish Cancer Society, 02 6661Wellcome trust
Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2017-11-29Bibliographically 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
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