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Whole-exome sequenc...
Whole-exome sequencing in relapsing chronic lymphocytic leukemia : clinical impact of recurrent RPS15 mutations
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- Ljungström, Viktor (author)
- Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Cortese, Diego (author)
- Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Young, Emma (author)
- Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Pandzic, Tatjana (author)
- Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi
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- Mansouri, Larry (author)
- Uppsala University,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Plevova, Karla (author)
- Masaryk University
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- Ntoufa, Stavroula (author)
- Center for Research and Technology Hellas
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- Baliakas, Panagiotis (author)
- Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Clifford, Ruth (author)
- University of Oxford
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- Sutton, Lesley-Ann (author)
- Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi
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Blakemore, Stuart (author)
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Stavroyianni, Niki (author)
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Agathangelidis, Andreas (author)
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Rossi, Davide (author)
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- Höglund, Martin (author)
- Uppsala universitet,Hematologi
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Kotaskova, Jana (author)
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- Juliusson, Gunnar (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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Belessi, Chrysoula (author)
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Chiorazzi, Nicholas (author)
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Panagiotidis, Panagiotis (author)
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Langerak, Anton W (author)
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- Smedby, Karin E (author)
- Karolinska Institutet
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Oscier, David (author)
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Gaidano, Gianluca (author)
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Schuh, Anna (author)
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Davi, Frederic (author)
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Pott, Christiane (author)
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Strefford, Jonathan C (author)
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Trentin, Livio (author)
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Pospisilova, Sarka (author)
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Ghia, Paolo (author)
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- Stamatopoulos, Kostas (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Sjöblom, Tobias (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi
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- Rosenquist, Richard (author)
- Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- American Society of Hematology, 2016
- 2016
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 127:8, s. 1007-1016
- Related links:
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http://www.ncbi.nlm....
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http://dx.doi.org/10...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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Blood
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- By the author/editor
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Ljungström, Vikt ...
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Cortese, Diego
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Young, Emma
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Pandzic, Tatjana
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Mansouri, Larry
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Plevova, Karla
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show more...
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Ntoufa, Stavroul ...
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Baliakas, Panagi ...
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Clifford, Ruth
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Sutton, Lesley-A ...
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Blakemore, Stuar ...
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Stavroyianni, Ni ...
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Agathangelidis, ...
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Rossi, Davide
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Höglund, Martin
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Kotaskova, Jana
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Juliusson, Gunna ...
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Belessi, Chrysou ...
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Chiorazzi, Nicho ...
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Panagiotidis, Pa ...
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Langerak, Anton ...
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Smedby, Karin E
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Oscier, David
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Gaidano, Gianluc ...
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Schuh, Anna
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Davi, Frederic
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Pott, Christiane
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Strefford, Jonat ...
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Trentin, Livio
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Pospisilova, Sar ...
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Ghia, Paolo
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Stamatopoulos, K ...
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Sjöblom, Tobias
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Rosenquist, Rich ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Blood
- By the university
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Uppsala University
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Lund University
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Karolinska Institutet