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Start Over Author "Young, Emma" Publisher uppsala universitet, experimentell och klinisk onkologi
19 results on '"Young, Emma"'

1. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

Author

Baliakas, Panagiotis, Moysiadis, Theodoros, Hadzidimitriou, Anastasia, Xochelli, Aliki, Jeromin, Sabine, Agathangelidis, Andreas, Mattsson, Mattias, Sutton, Lesley Ann, Minga, Eva, Scarfo, Lydia, Rossi, Davide, Davis, Zadie, Villamor, Neus, Parker, Helen, Kotaskova, Jana, Stalika, Evangelia, Plevova, Karla, Mansouri, Larry, Cortese, Diego, Navarro, Alba, Delgado, Julio, Larrayoz, Marta, Young, Emma, Anagnostopoulos, Achilles, Smedby, Karin E., Juliusson, Gunnar, Sheehy, Oonagh, Catherwood, Mark, Strefford, Jonathan C., Stavroyianni, Niki, Belessi, Chrysoula, Pospisilova, Sarka, Oscier, David, Gaidano, Gianluca, Campo, Elias, Haferlach, Claudia, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, Baliakas, Panagiotis, Moysiadis, Theodoros, Hadzidimitriou, Anastasia, Xochelli, Aliki, Jeromin, Sabine, Agathangelidis, Andreas, Mattsson, Mattias, Sutton, Lesley Ann, Minga, Eva, Scarfo, Lydia, Rossi, Davide, Davis, Zadie, Villamor, Neus, Parker, Helen, Kotaskova, Jana, Stalika, Evangelia, Plevova, Karla, Mansouri, Larry, Cortese, Diego, Navarro, Alba, Delgado, Julio, Larrayoz, Marta, Young, Emma, Anagnostopoulos, Achilles, Smedby, Karin E., Juliusson, Gunnar, Sheehy, Oonagh, Catherwood, Mark, Strefford, Jonathan C., Stavroyianni, Niki, Belessi, Chrysoula, Pospisilova, Sarka, Oscier, David, Gaidano, Gianluca, Campo, Elias, Haferlach, Claudia, Ghia, Paolo, Rosenquist, Richard, and Stamatopoulos, Kostas

Abstract

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.

Published
2019
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2. Recurrent Genetic Mutations in Lymphoid Malignancies

Author

Young, Emma

Subjects
Cancer och onkologi, PMBL, subsets, Hematology, stereotypy, mutations, Lymphoid malignancies, whole-genome sequencing, hemic and lymphatic diseases, Cancer and Oncology, EGR2, NFKBIE, Hematologi, CLL
Abstract

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.

Published
2017

3. DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS : A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?

Author

Bhoi, Sujata, Mansouri, Larry, Castellano, G., Sutton, Lesley Ann, Papakonstantinou, N., Queiros, A., Ek, S., Emruli, V. K., Plevova, K., Ntoufa, S., Davis, Z., Young, Emma, Göransson, Hanna, Isaksson, Anders, Smedby, K. E., Gaidano, G., Langerak, A. W., Davi, F., Rossi, D., Oscier, D., Pospisilova, S., Ghia, P., Campo, E., Stamatopoulos, K., Martin-Subero, J. -I, Rosenquist, Richard, Bhoi, Sujata, Mansouri, Larry, Castellano, G., Sutton, Lesley Ann, Papakonstantinou, N., Queiros, A., Ek, S., Emruli, V. K., Plevova, K., Ntoufa, S., Davis, Z., Young, Emma, Göransson, Hanna, Isaksson, Anders, Smedby, K. E., Gaidano, G., Langerak, A. W., Davi, F., Rossi, D., Oscier, D., Pospisilova, S., Ghia, P., Campo, E., Stamatopoulos, K., Martin-Subero, J. -I, and Rosenquist, Richard

Published
2017

4. T Cells In Chronic Lymphocytic Leukemia Display Dysregulated Expression Of Immune Checkpoints And Activation Markers

Author

Palma, Marzia, Gentilcore, Giusy, Heimersson, Kia, Mozaffari, Fariba, Näsman-Glaser, Barbro, Young, Emma, Rosenquist, Richard, Hansson, Lotta, Österborg, Anders, Mellstedt, Håkan, Palma, Marzia, Gentilcore, Giusy, Heimersson, Kia, Mozaffari, Fariba, Näsman-Glaser, Barbro, Young, Emma, Rosenquist, Richard, Hansson, Lotta, Österborg, Anders, and Mellstedt, Håkan

Abstract

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.

Published
2017
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5. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

Author

Young, Emma, Noerenberg, Daniel, Mansouri, Larry, Ljungström, Viktor, Frick, Mareike, Sutton, Lesley Ann, Blakemore, Stuart James, Galan-Sousa, Joel, Plevova, Karla, Baliakas, Panagiotis, Rossi, Davide, Ruth, Clifford, Roos-Weil, Damien, Navrklova, Veronika, Dörken, Bernd, Schmitt, Clemens A, Ekström Smedby, Karin, Juliusson, Gunnar, Giacopelli, Brian, Blachly, James, Belessi, Chrysoula, Panayiotidis, Panayiotis, Chiorazzi, Nicholas, Davi, Frédéric, Langerak, Anton W, Oscier, David, Schuh, Anna, Gaidano, Gianluca, Ghia, Paolo, Xu, Wei, Fan, Lei, Bernard, Olivier A, Nguyen-Khac, Florence, Rassenti, Laura Z, Li, Jianyonglm, Kipps, Thomas J, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Strefford, Jonathan, Rosenquist, Richard, Damm, Frederik, Young, Emma, Noerenberg, Daniel, Mansouri, Larry, Ljungström, Viktor, Frick, Mareike, Sutton, Lesley Ann, Blakemore, Stuart James, Galan-Sousa, Joel, Plevova, Karla, Baliakas, Panagiotis, Rossi, Davide, Ruth, Clifford, Roos-Weil, Damien, Navrklova, Veronika, Dörken, Bernd, Schmitt, Clemens A, Ekström Smedby, Karin, Juliusson, Gunnar, Giacopelli, Brian, Blachly, James, Belessi, Chrysoula, Panayiotidis, Panayiotis, Chiorazzi, Nicholas, Davi, Frédéric, Langerak, Anton W, Oscier, David, Schuh, Anna, Gaidano, Gianluca, Ghia, Paolo, Xu, Wei, Fan, Lei, Bernard, Olivier A, Nguyen-Khac, Florence, Rassenti, Laura Z, Li, Jianyonglm, Kipps, Thomas J, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Strefford, Jonathan, Rosenquist, Richard, and Damm, Frederik

Abstract

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., 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.

Published
2017
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6. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma

Author

Mansouri, Larry, Noerenberg, Daniel, Young, Emma, Mylonas, Elena, Abdulla, Maysaa, Frick, Mareike, Asmar, Fazila, Ljungström, Viktor, Schneider, Markus, Yoshida, Kenichi, Skaftason, Aron, Pandzic, Tatjana, Gonzalez, Blanca, Tasidou, Anna, Waldhueter, Nils, Rivas-Delgado, Alfredo, Angelopoulou, Maria, Ziepert, Marita, Arends, Christopher-Maximilian, Couronne, Lucile, Lenze, Dido, Claudia, Baldus, Bastard, Christian, Okosun, Jessica, Fitzgibbon, Jude, Dörken, Bernd, Drexler, Hans G, Roos-Weil, Damien, Schmitt, Clemens A, Munch-Petersen, Helga D, Zenz, Thorsten, Hansmann, Martin-Leo, Strefford, Jonathan C, Enblad, Gunilla, Bernard, Olivier, Ralfkiaer, Elisabeth, Erlanson, Martin, Korkolopoulou, Penelope, Hultdin, Magnus, Papadaki, Theodora, Grønbæk, Kirsten, Lopez-Guillermo, Armando, Ogawa, Seishi, Küppers, Ralf, Stamatopoulos, Kostas, Stavroyianni, Niki, Kanellis, George, Rosenwald, Andreas, Campo, Elias, Amini, Rose-Marie, Ott, German, Vasslakopoulos, Theodoros P, Hummel, Michael, Rosenquist, Richard, Damm, Frederik, Mansouri, Larry, Noerenberg, Daniel, Young, Emma, Mylonas, Elena, Abdulla, Maysaa, Frick, Mareike, Asmar, Fazila, Ljungström, Viktor, Schneider, Markus, Yoshida, Kenichi, Skaftason, Aron, Pandzic, Tatjana, Gonzalez, Blanca, Tasidou, Anna, Waldhueter, Nils, Rivas-Delgado, Alfredo, Angelopoulou, Maria, Ziepert, Marita, Arends, Christopher-Maximilian, Couronne, Lucile, Lenze, Dido, Claudia, Baldus, Bastard, Christian, Okosun, Jessica, Fitzgibbon, Jude, Dörken, Bernd, Drexler, Hans G, Roos-Weil, Damien, Schmitt, Clemens A, Munch-Petersen, Helga D, Zenz, Thorsten, Hansmann, Martin-Leo, Strefford, Jonathan C, Enblad, Gunilla, Bernard, Olivier, Ralfkiaer, Elisabeth, Erlanson, Martin, Korkolopoulou, Penelope, Hultdin, Magnus, Papadaki, Theodora, Grønbæk, Kirsten, Lopez-Guillermo, Armando, Ogawa, Seishi, Küppers, Ralf, Stamatopoulos, Kostas, Stavroyianni, Niki, Kanellis, George, Rosenwald, Andreas, Campo, Elias, Amini, Rose-Marie, Ott, German, Vasslakopoulos, Theodoros P, Hummel, Michael, Rosenquist, Richard, and Damm, Frederik

Abstract

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., 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.

Published
2016
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7. Whole-exome sequencing in relapsing chronic lymphocytic leukemia : clinical impact of recurrent RPS15 mutations

Author

Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, Karla, Ntoufa, Stavroula, Baliakas, Panagiotis, Clifford, Ruth, Sutton, Lesley-Ann, Blakemore, Stuart, Stavroyianni, Niki, Agathangelidis, Andreas, Rossi, Davide, Höglund, Martin, Kotaskova, Jana, Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, Panagiotidis, Panagiotis, Langerak, Anton W, Smedby, Karin E, Oscier, David, Gaidano, Gianluca, Schuh, Anna, Davi, Frederic, Pott, Christiane, Strefford, Jonathan C, Trentin, Livio, Pospisilova, Sarka, Ghia, Paolo, Stamatopoulos, Kostas, Sjöblom, Tobias, Rosenquist, Richard, Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, Karla, Ntoufa, Stavroula, Baliakas, Panagiotis, Clifford, Ruth, Sutton, Lesley-Ann, Blakemore, Stuart, Stavroyianni, Niki, Agathangelidis, Andreas, Rossi, Davide, Höglund, Martin, Kotaskova, Jana, Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, Panagiotidis, Panagiotis, Langerak, Anton W, Smedby, Karin E, Oscier, David, Gaidano, Gianluca, Schuh, Anna, Davi, Frederic, Pott, Christiane, Strefford, Jonathan C, Trentin, Livio, Pospisilova, Sarka, Ghia, Paolo, Stamatopoulos, Kostas, Sjöblom, Tobias, and Rosenquist, Richard

Abstract

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., De två första författarna delar förstaförfattarskapet.De två sista författarna delar sistaförfattarskapet.

Published
2016
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8. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Author

Sutton, Lesley-Ann, Young, Emma, Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Moysiadis, Theodoros, Plevova, Karla, Rossi, Davide, Kminkova, Jana, Stalika, Evangelia, Pedersen, Lone Bredo, Malcikova, Jitka, Agathangelidis, Andreas, Davis, Zadie, Mansouri, Larry, Scarfo, Lydia, Boudjoghra, Myriam, Navarro, Alba, Muggen, Alice F., Yan, Xiao-Jie, Nguyen-Khac, Florence, Larrayoz, Marta, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Niemann, Carsten Utoft, Belessi, Chrysoula, Campo, Elias, Strefford, Jonathan C., Langerak, Anton W., Oscier, David, Gaidano, Gianluca, Pospisilova, Sarka, Davi, Frederic, Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Sutton, Lesley-Ann, Young, Emma, Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Moysiadis, Theodoros, Plevova, Karla, Rossi, Davide, Kminkova, Jana, Stalika, Evangelia, Pedersen, Lone Bredo, Malcikova, Jitka, Agathangelidis, Andreas, Davis, Zadie, Mansouri, Larry, Scarfo, Lydia, Boudjoghra, Myriam, Navarro, Alba, Muggen, Alice F., Yan, Xiao-Jie, Nguyen-Khac, Florence, Larrayoz, Marta, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Niemann, Carsten Utoft, Belessi, Chrysoula, Campo, Elias, Strefford, Jonathan C., Langerak, Anton W., Oscier, David, Gaidano, Gianluca, Pospisilova, Sarka, Davi, Frederic, Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

Abstract

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

Published
2016
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9. ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia : enrichment in subset #2 is associated with markedly short telomeres

Author

Navrkalova, Veronika, Young, Emma, Baliakas, Panagiotis, Radova, Lenka, Sutton, Lesley-Ann, Plevova, Karla, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagiotis, Touloumenidou, Tasoula, Davi, Frederic, Langerak, Anton W., Ghia, Paolo, Strefford, Jonathan C., Oscier, David, Mayer, Jiri, Stamatopoulos, Kostas, Pospisilova, Sarka, Rosenquist, Richard, Trbusek, Martin, Navrkalova, Veronika, Young, Emma, Baliakas, Panagiotis, Radova, Lenka, Sutton, Lesley-Ann, Plevova, Karla, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagiotis, Touloumenidou, Tasoula, Davi, Frederic, Langerak, Anton W., Ghia, Paolo, Strefford, Jonathan C., Oscier, David, Mayer, Jiri, Stamatopoulos, Kostas, Pospisilova, Sarka, Rosenquist, Richard, and Trbusek, Martin

Published
2016
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10. Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia

Author

Mansouri, Larry, Sutton, Lesley-Ann, Ljungström, Viktor, Bondza, Sina, Arngården, Linda, Bhoi, Sujata, Larsson, Jimmy, Cortese, Diego, Kalushkova, Antonia, Plevova, Karla, Young, Emma, Gunnarsson, Rebeqa, Falk Sörqvist, Elin, Lönn, Peter, Muggen, Alice F., Yan, Xiao-Jie, Sander, Birgitta, Enblad, Gunilla, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Rung, Johan, Chiorazzi, Nicholas, Strefford, Jonathan C., Langerak, Anton W., Pospisilova, Sarka, Davi, Frederic, Hellström, Mats, Jernberg Wiklund, Helena, Ghia, Paolo, Söderberg, Ola, Stamatopoulos, Kostas, Nilsson, Mats, Rosenquist Brandell, Richard, Mansouri, Larry, Sutton, Lesley-Ann, Ljungström, Viktor, Bondza, Sina, Arngården, Linda, Bhoi, Sujata, Larsson, Jimmy, Cortese, Diego, Kalushkova, Antonia, Plevova, Karla, Young, Emma, Gunnarsson, Rebeqa, Falk Sörqvist, Elin, Lönn, Peter, Muggen, Alice F., Yan, Xiao-Jie, Sander, Birgitta, Enblad, Gunilla, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Rung, Johan, Chiorazzi, Nicholas, Strefford, Jonathan C., Langerak, Anton W., Pospisilova, Sarka, Davi, Frederic, Hellström, Mats, Jernberg Wiklund, Helena, Ghia, Paolo, Söderberg, Ola, Stamatopoulos, Kostas, Nilsson, Mats, and Rosenquist Brandell, Richard

Abstract

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

Published
2015
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11. Targeted next-generation sequencing in chronic lymphocytic leukemia : a high-throughput yet tailored approach will facilitate implementation in a clinical setting

Author

Sutton, Lesley-Ann, Ljungström, Viktor, Mansouri, Larry, Young, Emma, Cortese, Diego, Navrkalova, Veronika, Malcikova, Jitka, Muggen, Alice F., Trbusek, Martin, Panagiotidis, Panagiotis, Davi, Frederic, Belessi, Chrysoula, Langerak, Anton W., Ghia, Paolo, Pospisilova, Sarka, Stamatopoulos, Kostas, Rosenquist, Richard Brandell, Sutton, Lesley-Ann, Ljungström, Viktor, Mansouri, Larry, Young, Emma, Cortese, Diego, Navrkalova, Veronika, Malcikova, Jitka, Muggen, Alice F., Trbusek, Martin, Panagiotidis, Panagiotis, Davi, Frederic, Belessi, Chrysoula, Langerak, Anton W., Ghia, Paolo, Pospisilova, Sarka, Stamatopoulos, Kostas, and Rosenquist, Richard Brandell

Abstract

Next- generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re- sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features ( unmutated IGHV, n= 137; IGHV3- 21 subset # 2, n= 51) were sequenced on the HiSeq 2000 and data were analyzed using well- established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/ 180 ( 63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/ 177 ( 84%) of all mutations. We selected 155 mutations for Sanger validation ( variant allele frequency, 10- 99%) and 93% ( 144/ 155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11- 27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/ 82 ( 94%) mutations. In summary, this study demonstrates that targeted next- generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand- alone test without the need for confirmation by Sanger sequencing., De två första författarna delar förstaförfattarskapet.

Published
2015
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12. DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING : IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION

Author

Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, K., Sutton, L. A., Stavroyianni, N., Agathangelidis, A., Rossi, D., Höglund, Martin, Oscier, D., Gaidano, G., Davi, F., Pott, C., Trentin, L., Pospisilova, S., Ghia, P., Stamatopoulos, Kostas, Sjöblom, Tobias, Rosenquist, Richard, Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, K., Sutton, L. A., Stavroyianni, N., Agathangelidis, A., Rossi, D., Höglund, Martin, Oscier, D., Gaidano, G., Davi, F., Pott, C., Trentin, L., Pospisilova, S., Ghia, P., Stamatopoulos, Kostas, Sjöblom, Tobias, and Rosenquist, Richard

Published
2015

13. ATM Mutations in Major Stereotyped CLL Subsets : Enrichment in Subset #2 is Associated with Unfavourable Outcome

Author

Navrkalova, Veronika, Young, Emma, Baliakas, Panagiotis, Radova, Lenka, Plevova, Karla, Sutton, Lesley-Ann, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagiotis, Davi, Frederic, Langerak, Anton W., Ghia, Paolo, Strefford, Jonathan C., Oscier, David G., Stamatopoulos, Kostas, Pospisilova, Sarka, Rosenquist, Richard, Trbusek, Martin, Navrkalova, Veronika, Young, Emma, Baliakas, Panagiotis, Radova, Lenka, Plevova, Karla, Sutton, Lesley-Ann, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagiotis, Davi, Frederic, Langerak, Anton W., Ghia, Paolo, Strefford, Jonathan C., Oscier, David G., Stamatopoulos, Kostas, Pospisilova, Sarka, Rosenquist, Richard, and Trbusek, Martin

Published
2015

14. EGR2 Mutations in Chronic Lymphocytic Leukemia : A New Bad Player

Author

Noerenberg, Daniel, Young, Emma, Ljungström, Viktor, Mansouri, Larry, Plevova, Karla, Baliakas, Panagiotis, Blakemore, Stuart, Rossi, Davide, Clifford, Ruth, Navrkalova, Veronika, Sutton, Lesley-Ann, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Davi, Frederic, Langerak, Anton W., Schuh, Anna, Gaidano, Gianluca, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Rosenquist, Richard, Damm, Frederik, Noerenberg, Daniel, Young, Emma, Ljungström, Viktor, Mansouri, Larry, Plevova, Karla, Baliakas, Panagiotis, Blakemore, Stuart, Rossi, Davide, Clifford, Ruth, Navrkalova, Veronika, Sutton, Lesley-Ann, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Davi, Frederic, Langerak, Anton W., Schuh, Anna, Gaidano, Gianluca, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Rosenquist, Richard, and Damm, Frederik

Published
2015

15. EGR2 mutations in chronic lymphocytic leukemiam - a new bad player?

Author

Young, Emma, Norenberg, Daniel, Ljungstrom, Viktor, Mansouri, Larry, Plevova, Karla, Baliakas, Panagiotis, Rossi, Davide, Navrkalova, Veronika, Sutton, Lesley-Ann, Smedby, Karin Ekstrom, Juliusson, Gunnar, Belessi, Chrysoula, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Davi, Frederic, Langerak, Anton W., Gaidano, Gianluca, Ghia, Paolo, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Rosenquist, Richard, Damm, Frederik, Young, Emma, Norenberg, Daniel, Ljungstrom, Viktor, Mansouri, Larry, Plevova, Karla, Baliakas, Panagiotis, Rossi, Davide, Navrkalova, Veronika, Sutton, Lesley-Ann, Smedby, Karin Ekstrom, Juliusson, Gunnar, Belessi, Chrysoula, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Davi, Frederic, Langerak, Anton W., Gaidano, Gianluca, Ghia, Paolo, Stamatopoulos, Kostas, Pospisilova, Sarka, Zenz, Thorsten, Rosenquist, Richard, and Damm, Frederik

Abstract

Meeting Abstract: 103

Published
2015

16. Subset-Specific Spectra of Recurrent Gene Mutations in Chronic Lymphocytic Leukemia with Stereotyped B-Cell Receptors

Author

Sutton, Lesley-Ann, Young, Emma, Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Plevova, Karla, Rossi, Davide, Malcikova, Jitka, Stalika, Evangelia, Pedersen, Lone Bredo, Agathangelidis, Andreas, Davis, Zadie, Mansouri, Larry, Scarfo, Lydia, Boudjogra, Myriam, Navarro, Alba, Muggen, Alice, Yan, Xiao-Jie, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Geisler, Christian, Belessi, Chrysoula, Campo, Elias, Stretford, Jonathan C., Ghia, Paolo, Langerak, Anton W., Oscier, David, Gaidano, Gianluca, Pospisilova, Sarka, Davi, Frederic, Stamatopoulos, Kostas, Rosenquist, Richard Brandell, Sutton, Lesley-Ann, Young, Emma, Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Plevova, Karla, Rossi, Davide, Malcikova, Jitka, Stalika, Evangelia, Pedersen, Lone Bredo, Agathangelidis, Andreas, Davis, Zadie, Mansouri, Larry, Scarfo, Lydia, Boudjogra, Myriam, Navarro, Alba, Muggen, Alice, Yan, Xiao-Jie, Panagiotidis, Panagiotis, Chiorazzi, Nicholas, Geisler, Christian, Belessi, Chrysoula, Campo, Elias, Stretford, Jonathan C., Ghia, Paolo, Langerak, Anton W., Oscier, David, Gaidano, Gianluca, Pospisilova, Sarka, Davi, Frederic, Stamatopoulos, Kostas, and Rosenquist, Richard Brandell

Published
2014

17. Recurrent Mutations within the Nfkbie gene : A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia

Author

Mansouri, Larry, Sutton, Lesley-Ann, Ljungström, Viktor, Bondza, Sina, Arngården, Linda, Bhoi, Sujata, Larsson, Jimmy, Cortese, Diego, Kalushkova, Antonia, Gunnarsson, Rebeqa, Young, Emma, Falk-Sörqvist, Elin, Plevova, Karla, Muggen, Alice, Yan, Xiao-Jie, Sander, Birgitta, Enblad, Gunilla, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, Strefford, Jonathan C., Langerak, Anton W., Pospisilova, Sarka, Davi, Frederic, Hellström, Mats, Wiklund, Helena Jernberg, Ghia, Paolo, Söderberg, Ola, Stamatopoulos, Kostas, Nilsson, Mats, Rosenquist, Richard, Mansouri, Larry, Sutton, Lesley-Ann, Ljungström, Viktor, Bondza, Sina, Arngården, Linda, Bhoi, Sujata, Larsson, Jimmy, Cortese, Diego, Kalushkova, Antonia, Gunnarsson, Rebeqa, Young, Emma, Falk-Sörqvist, Elin, Plevova, Karla, Muggen, Alice, Yan, Xiao-Jie, Sander, Birgitta, Enblad, Gunilla, Smedby, Karin E., Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, Strefford, Jonathan C., Langerak, Anton W., Pospisilova, Sarka, Davi, Frederic, Hellström, Mats, Wiklund, Helena Jernberg, Ghia, Paolo, Söderberg, Ola, Stamatopoulos, Kostas, Nilsson, Mats, and Rosenquist, Richard

Published
2014

19. Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Author

Ljungström, Viktor, Young, Emma, Agathangelidis, Andreas, Muggen, Alice F., Plevova, Karla, Rossi, Davide, Davis, Zadie, Sutton, Lesley-Ann, Baliakas, Panagiotis, Ntoufa, Stavroula, Davi, Frederic, Gaidano, Gianluca, Oscier, David, Pospisilova, Sarka, Langerak, Anton W., Stamatopoulos, Kostas, Ghia, Paolo, Rosenquist, Richard, Ljungström, Viktor, Young, Emma, Agathangelidis, Andreas, Muggen, Alice F., Plevova, Karla, Rossi, Davide, Davis, Zadie, Sutton, Lesley-Ann, Baliakas, Panagiotis, Ntoufa, Stavroula, Davi, Frederic, Gaidano, Gianluca, Oscier, David, Pospisilova, Sarka, Langerak, Anton W., Stamatopoulos, Kostas, Ghia, Paolo, and Rosenquist, Richard

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