uu.seUppsala University Publications
Change search
Refine search result
1 - 14 of 14
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Minga, E.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Scarfo, L.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Agathangelidis, A.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Villamor, N.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain..
    Parker, H.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Kotaskova, J.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Stalika, E.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navarro Lopez, A.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain..
    Delgado, J.
    Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain..
    Larrayoz, M.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Smedby, K. E.
    Dept Med, Solna, Sweden.;Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Juliusson, G.
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Strefford, J. C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Campo, E.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain.;Univ Barcelona, Dept Pathol, Barcelona, Spain..
    Ghia, P.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 52-52Article in journal (Other academic)
  • 2.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hadzidimitriou, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rossi, D
    Minga, E
    Villamor, N
    Larrayoz, M
    Kminkova, J
    Agathangelidis, A
    Davis, Z
    Tausch, E
    Stalika, E
    Kantorova, B
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfò, L
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, V
    Rose-Zerilli, M J J
    Smedby, K E
    Juliusson, G
    Anagnostopoulos, A
    Makris, A M
    Navarro, A
    Delgado, J
    Oscier, D
    Belessi, C
    Stilgenbauer, S
    Ghia, P
    Pospisilova, S
    Gaidano, G
    Campo, E
    Strefford, J C
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Recurrent mutations refine prognosis in chronic lymphocytic leukemia2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, p. 329-336Article in journal (Refereed)
    Abstract [en]

    Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

  • 3.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Moysiadis, Theodoros
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Jeromin, Sabine
    MLL Munich Leukemia Lab, Munich, Germany.
    Agathangelidis, Andreas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Minga, Eva
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Scarfo, Lydia
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Rossi, Davide
    Oncol Inst Southern Switzerland, Bellinzona, Switzerland.
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Villamor, Neus
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain.
    Parker, Helen
    Univ Southampton, Canc Res UK Ctr, Acad Unit Canc Sci, Canc Genon, Southampton, Hants, England;Univ Southampton, Fac Med, Expt Canc Med Ctr, Southampton, Hants, England.
    Kotaskova, Jana
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Stalika, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cortese, Diego
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Navarro, Alba
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain.
    Delgado, Julio
    Hosp Clin Barcelona, Hematol Dept, Barcelona, Spain.
    Larrayoz, Marta
    Univ Southampton, Canc Res UK Ctr, Acad Unit Canc Sci, Canc Genon, Southampton, Hants, England;Univ Southampton, Fac Med, Expt Canc Med Ctr, Southampton, Hants, England.
    Young, Emma
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.
    Juliusson, Gunnar
    Lund Univ & Hosp, Lund Stem Cell Ctr, Dept Hematol, Lund, Sweden.
    Sheehy, Oonagh
    Belfast City Hosp, Dept Hematooncol, Belfast, Antrim, North Ireland.
    Catherwood, Mark
    Belfast City Hosp, Dept Hematooncol, Belfast, Antrim, North Ireland.
    Strefford, Jonathan C.
    Univ Southampton, Canc Res UK Ctr, Acad Unit Canc Sci, Canc Genon, Southampton, Hants, England;Univ Southampton, Fac Med, Expt Canc Med Ctr, Southampton, Hants, England.
    Stavroyianni, Niki
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece.
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Gaidano, Gianluca
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy.
    Campo, Elias
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain;Univ Barcelona, Dept Pathol, Barcelona, Spain.
    Haferlach, Claudia
    MLL Munich Leukemia Lab, Munich, Germany.
    Ghia, Paolo
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Stamatopoulos, Kostas
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.
    Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 2, p. 360-369Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 4.
    Bhoi, Sujata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sevov, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Smedby, Karin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Juliusson, Gunnar
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. E63-E65Article in journal (Refereed)
  • 5.
    Cortese, Diego
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sutton, Lesley Ann
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smedby, K E
    Geisler, C
    Gunnarsson, R
    Juliusson, G
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    On the way towards a 'CLL prognostic index': focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort.2014In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 3, p. 710-713Article in journal (Refereed)
  • 6.
    Ljungström, Viktor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plevova, K.
    Masaryk Univ, Dept Mol Med, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stavroyianni, N.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Agathangelidis, A.
    Ist Sci San Raffaele, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy..
    Davi, F.
    Hop Cochin, Hematol Lab, F-75674 Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Pott, C.
    Univ Hosp Schleswig Holstein, Med Dept 2, Kiel, Germany..
    Trentin, L.
    Univ Padua, Sch Med, Dept Med, Hematol & Clin Immunol Branch, Padua, Italy..
    Pospisilova, S.
    Masaryk Univ, Dept Mol Med, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Ghia, P.
    Ist Sci San Raffaele, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 10-11Article in journal (Other academic)
  • 7.
    Ljungström, Viktor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Ntoufa, Stavroula
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clifford, Ruth
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Blakemore, Stuart
    Stavroyianni, Niki
    Agathangelidis, Andreas
    Rossi, Davide
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    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
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöblom, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 8, p. 1007-1016Article in journal (Refereed)
    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.

  • 8.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Falk-Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Plevova, Karla
    Muggen, Alice
    Yan, Xiao-Jie
    Sander, Birgitta
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Juliusson, Gunnar
    Belessi, Chrysoula
    Chiorazzi, Nicholas
    Strefford, Jonathan C.
    Langerak, Anton W.
    Pospisilova, Sarka
    Davi, Frederic
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 9.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cortese, Diego
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falk Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Muggen, Alice F.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Yan, Xiao-Jie
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America, .
    Sander, Birgitta
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Rung, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chiorazzi, Nicholas
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
    Strefford, Jonathan C.
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Langerak, Anton W.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Davi, Frederic
    AP-HP, Hôpital Pitié-Salpêtrière, Department of Hematology, and Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
    Hellström, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Division of Experimental Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
    Söderberg, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. nstitute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Rosenquist Brandell, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia2015In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 10.
    Rosenquist Brandell, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand?2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 11, p. 2351-2364Article, review/survey (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease where the majority of patients have an indolent disease course, while others may experience a far more aggressive disease, treatment failure and poor overall survival. During the last two decades, there has been an intense search to find novel biomarkers that can predict prognosis as well as guide treatment decisions. Two of the most reliable molecular prognostic markers, both of which are offered in routine diagnostics, are the immunoglobulin heavy chain variable (IGHV) gene mutational status and fluorescence in situ hybridization (FISH) detection of prognostically relevant genomic aberrations (e.g. 11q-, 13q-, +12 and 17p-). In addition to these markers, a myriad of additional biomarkers have been postulated as potential prognosticators in CLL, on the protein (e.g. CD38, ZAP70, TCL1), the RNA (e.g. LPL, CLLU1, micro-RNAs) and the genomic (e.g. TP53, NOTCH1, SF3B1 and BIRC3 mutations) level. Efforts are now being made to test these novel markers in larger patient cohorts as well as in prospective trials, with the ultimate goal to combine the "best" markers in a "CLL prognostic index" applicable for the individual patient. Although it is clear that these studies have significantly improved our knowledge regarding both prognostication and the biology of the disease, there is still an immediate need for recognizing biomarkers that can predict therapy response, and efforts should now focus on addressing this pertinent issue. In the present article, we review the extensive literature in the field of prognostic markers in CLL, focus on the most clinically relevant markers and discuss future directions regarding biomarkers in CLL.

  • 11. Strefford, J. C.
    et al.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Agathangelidis, A.
    Malcikova, J.
    Plevova, K.
    Scarfo, L.
    Davis, Z.
    Stalika, E.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pedersen, L. B.
    di Celle, P. F.
    Tzenou, T.
    Geisler, C.
    Panagiotidis, P.
    Langerak, A. W.
    Chiorazzi, N.
    Pospisilova, S.
    Oscier, D.
    Davi, F.
    Belessi, C.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ghia, P.
    Stamatopoulos, K.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #22013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 11, p. 2196-2199Article in journal (Refereed)
    Abstract [en]

    Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset # 2 was only 8%, lower than the frequency observed in either subset # 1 or # 8 (19% and 14%, respectively; P 0.04 for subset # 1 versus # 2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.

  • 12.
    Sutton, L. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, V.
    Malcikova, J.
    Muggen, A. F.
    Trbusek, M.
    Davi, F.
    Belessi, C.
    Langerak, A. W.
    Ghia, P.
    Pospisilova, S.
    Stamatopoulos, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, R.
    Targeted Next-Generation Sequencing for Mutational Screening in Chronic Lymphocytic Leukemia: A High-Throughput Yet Tailored Approach Will Facilitate Implementation Within a Clinical Setting2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 313-314Article in journal (Other academic)
  • 13.
    Sutton, Lesley Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol CEITEC, Brno, Czech Republic.
    Rossi, Davide
    Oncol Inst Southern Switzerland, Brno, Czech Republic.
    Stalika, Evangelia
    CERTH, Thermi, Greece.
    Agathangelidis, Andreas
    CERTH, Thermi, Greece.
    Scarfo, Lydia
    Osped San Raffaele, Milan, Italy.
    Muggen, Alice F.
    ErasmusMC, Rotterdam, Netherlands.
    Langerak, Anton W.
    ErasmusMC, Rotterdam, Netherlands.
    Pospisilova, Sarka
    Masaryk Univ, CEITEC, Brno, Czech Republic; Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic; Med Fac MU, Brno, Czech Republic.
    Davi, Frederic
    AP HP, Paris, France.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Milan, Italy.
    Stamatopoulos, Kostas
    IRCCS Ist Sci San Raffaele, Milan, Italy; Ctr Res & Technol Hellas, Thessaloniki, Greece.
    Brandell, Richard Rosenquist
    Karolinska Inst, Stockholm, Sweden.
    Transcriptome sequencing provides novel insights into the biology of chronic lymphocytic leukemia: focus on major stereotyped subsets2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no Supplement: 1, p. 220-221Article in journal (Other academic)
  • 14.
    Sutton, Lesley-Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, Veronika
    Malcikova, Jitka
    Muggen, Alice F.
    Trbusek, Martin
    Panagiotidis, Panagiotis
    Davi, Frederic
    Belessi, Chrysoula
    Langerak, Anton W.
    Ghia, Paolo
    Pospisilova, Sarka
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting2015In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, no 3, p. 370-376Article in journal (Refereed)
    Abstract [en]

    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.

1 - 14 of 14
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf