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Young, Emma
Publications (10 of 16) Show all publications
Baliakas, P., Moysiadis, T., Hadzidimitriou, A., Xochelli, A., Jeromin, S., Agathangelidis, A., . . . Stamatopoulos, K. (2019). Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia. Haematologica, 104(2), 360-369
Open this publication in new window or tab >>Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 2, p. 360-369Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to first -treatment and a treatment probability at Five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or ST3B1 mutations were associated with the shortest time-to-First treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2019
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377215 (URN)10.3324/haematol.2018.195032 (DOI)000457460800032 ()30262567 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Bhoi, S., Mansouri, L., Castellano, G., Sutton, L. A., Papakonstantinou, N., Queiros, A., . . . Rosenquist, R. (2017). DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?. Paper presented at 22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN. Haematologica, 102(Suppl. 2), 68-68, Article ID P244.
Open this publication in new window or tab >>DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 68-68, article id P244Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377412 (URN)000404127001140 ()
Conference
22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Young, E. (2017). Recurrent Genetic Mutations in Lymphoid Malignancies. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Recurrent Genetic Mutations in Lymphoid Malignancies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 82
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1312
Keywords
Lymphoid malignancies, mutations, CLL, stereotypy, subsets, PMBL, NFKBIE, EGR2, whole-genome sequencing
National Category
Cancer and Oncology Hematology
Research subject
Molecular Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-314956 (URN)978-91-554-9850-4 (ISBN)
Public defence
2017-05-05, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-04-07 Created: 2017-03-13 Last updated: 2017-04-21
Palma, M., Gentilcore, G., Heimersson, K., Mozaffari, F., Näsman-Glaser, B., Young, E., . . . Mellstedt, H. (2017). T Cells In Chronic Lymphocytic Leukemia Display Dysregulated Expression Of Immune Checkpoints And Activation Markers. Haematologica, 102(3), 562-572
Open this publication in new window or tab >>T Cells In Chronic Lymphocytic Leukemia Display Dysregulated Expression Of Immune Checkpoints And Activation Markers
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no 3, p. 562-572Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+ cells and the CD8+ subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+ and CD8+ cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+ and CD8+ subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+ and CD8+ cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+ and CD8+ cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways.

Keywords
SURFACE EXPRESSION; PERIPHERAL-BLOOD; CD152 CTLA-4; CLL PATIENTS; B-CLL; EXPANSION; SUBSETS; STAGE; PD-1; LENALIDOMIDE
National Category
Hematology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-318346 (URN)10.3324/haematol.2016.151100 (DOI)000402485700031 ()27927767 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilCancer and Allergy Foundation
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-01-03Bibliographically approved
Navrkalova, V., Young, E., Baliakas, P., Radova, L., Sutton, L.-A., Plevova, K., . . . Trbusek, M. (2016). ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres [Letter to the editor]. Haematologica, 101(9), Article ID e372.
Open this publication in new window or tab >>ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 9, article id e372Article in journal, Letter (Refereed) Published
Keywords
chronic lymphocytic leukemia, stereotyped subset, ATM mutation, short telomere, antigenic selection
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-316640 (URN)10.3324/haematol.2016.142968 (DOI)000392547200020 ()27479817 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilEU, European Research Council
Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-11-29Bibliographically approved
Mansouri, L., Noerenberg, D., Young, E., Mylonas, E., Abdulla, M., Frick, M., . . . Damm, F. (2016). Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood, 128(23), 2666-2670
Open this publication in new window or tab >>Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed) Published
Abstract [en]

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

National Category
Hematology Clinical Laboratory Medicine
Research subject
Molecular Genetics; Pathology
Identifiers
urn:nbn:se:uu:diva-314939 (URN)10.1182/blood-201603-704528 (DOI)000392652300015 ()27670424 (PubMedID)
Funder
German Research Foundation (DFG), DA1787/1-1Swedish Cancer SocietySwedish Research Council
Note

L.M., D.N., and E.Y. 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: 2020-01-03Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2016). Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood, 127(8), 1007-1016
Open this publication in new window or tab >>Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 8, p. 1007-1016Article in journal (Refereed) Published
Abstract [en]

Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-257013 (URN)10.1182/blood-2015-10-674572 (DOI)000373397800011 ()26675346 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilEU, European Research CouncilSwedish National Infrastructure for Computing (SNIC)
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2015-06-29 Created: 2015-06-29 Last updated: 2018-01-11Bibliographically approved
Navrkalova, V., Young, E., Baliakas, P., Radova, L., Plevova, K., Sutton, L.-A., . . . Trbusek, M. (2015). ATM Mutations in Major Stereotyped CLL Subsets: Enrichment in Subset #2 is Associated with Unfavourable Outcome. Paper presented at 57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL. Blood, 126(23)
Open this publication in new window or tab >>ATM Mutations in Major Stereotyped CLL Subsets: Enrichment in Subset #2 is Associated with Unfavourable Outcome
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-284663 (URN)000368019005190 ()
Conference
57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2015). DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION. Paper presented at 20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA. Haematologica, 100, 10-11
Open this publication in new window or tab >>DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION
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2015 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 10-11Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-266165 (URN)000361204901021 ()
Conference
20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA
Available from: 2015-11-11 Created: 2015-11-05 Last updated: 2017-12-01Bibliographically approved
Noerenberg, D., Young, E., Ljungström, V., Mansouri, L., Plevova, K., Baliakas, P., . . . Damm, F. (2015). EGR2 Mutations in Chronic Lymphocytic Leukemia: A New Bad Player. Paper presented at 57th Annual Meeting of the American-Society-of-Hematology, Orlando, FL, DEC 05-08, 2015. Blood, 126(23)
Open this publication in new window or tab >>EGR2 Mutations in Chronic Lymphocytic Leukemia: A New Bad Player
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-283004 (URN)000368021801068 ()
Conference
57th Annual Meeting of the American-Society-of-Hematology, Orlando, FL, DEC 05-08, 2015
Available from: 2016-04-13 Created: 2016-04-08 Last updated: 2017-11-30Bibliographically approved
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