期刊
BLOOD
卷 127, 期 8, 页码 1007-1016出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-10-674572
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资金
- Swedish Cancer Society
- Swedish Research Council
- Uppsala University, Uppsala University Hospital
- Lion's Cancer Research Foundation
- Selander's Foundation, Uppsala, Sweden
- Czech Ministry of Education, Youth and Sports [CZ.1.05/1.1.00/02.0068]
- Internal Grant Agency of the Czech Ministry of Health [NT13493-4/2012]
- Czech Ministry of Health [AZV 15-31834A]
- Kay Kendall Leukemia Fund
- Leukemia and Lymphoma Research
- Cancer Research UK
- Bournemouth Leukemia Fund
- Wessex Medical Research
- Associazione Italiana per la Ricerca sul Cancro (AIRC) investigator grant
- Special Program Molecular Clinical Oncology, Milano, Italy [9965, 10007]
- Ricerca Finalizzata [2318823]
- Progetto Giovani Ricercatori, Ministero della Salute, Rome, Italy [GR-2010-2317594]
- PRIN
- Ministero dell'Istruzione, dell'Universita e della Ricerca, Rome, Italy
- Progetto di Ateneo, Universita di Padova, Italy
- European Commission
- Swedish National Infrastructure for Computing through Uppsala Multidisciplinary Center for Advanced Computational Science [b2013136]
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although 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, and 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 before 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 with wild-type 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.
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