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Frequent somatic mutations in components of the RNA processing machinery in chronic lymphocytic leukemia

Leukemia volume 27, pages 1600–1603 (2013)Cite this article

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Chronic lymphocytic leukemia (CLL) is a common neoplasia of B lymphocytes with a heterogeneous clinical course ranging from an indolent disorder, with a normal lifespan, to an aggressive disease and short survival.1 The genetic mutations and associated molecular alterations that are able to accurately recapitulate the molecular pathogenesis of CLL are only now coming to light.2, 3, 4, 5 Foremost amongst the mutated genes is SF3B1, a core component of the RNA splicing machinery. SF3B1 mutations were found to be somatically acquired in ∼10% of CLL patients, and correlate with a more aggressive behavior of the disease.4, 5, 6, 7 Consistently, the recent identification in myeloid neoplasms of recurrent mutations in SF3B1 and other spliceosome components in a mutually exclusive manner suggests a common functional consequence in the regulation of RNA splicing.8, 9, 10

Virtually all of the eukaryotic mRNAs are synthesized as precursor molecules that need to be extensively processed in order to serve as a blueprint for proteins. The most prevalent steps are the capping reaction at the 5′-end, the removal of intervening sequences by splicing, formation of 3′-end poly (A)-tails and the nuclear export of the generated mature mRNA. Other RNA molecules undergo some of these maturation steps. Thus, 5′-end capping and transport to the cytosol are necessary to produce functional small nuclear ribonucleoproteins (snRNP), which in turn catalyze mRNA splicing.11 Although these maturation steps affect most transcripts in the cell, deregulation of splicing has recently been recognized as a driver of oncogenic processes.12 Moreover, it has been shown that the anti-tumoral mechanism of the drug spliceostatin A involves altered fidelity of splice-site recognition and changes in alternative splicing, particularly of cell-cycle-control genes.13 With these antecedents, we observed that the list of the 60 genes with the highest corrected mutational frequencies in CLL (RM-CLL genes class 1) contained four genes encoding factors, which has known roles in RNA splicing (SF3B1, SFRS1/SRSF1, U2AF65/U2AF2 and BRUNOL4/CELF4).4 In addition, we found three genes encoding RNA-export-machinery factors (NXF1, XPO1 and DDX3X).4 This prompted us to investigate the role of mutations affecting the RNA processing machinery, not limited to splicing, in the development of CLL.

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Acknowledgements

This work was funded by the Spanish Ministry of Science and Innovation (MICINN) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII. CL-O is an Investigator of the Botín Foundation. We are grateful to all members of the CLL Spanish Consortium for their continuous support to this project. We are also very grateful to all patients with CLL who have participated in this study.

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

    A J Ramsay, D Rodríguez, A Kwarciak, X S Puente, C López-Otín & V Quesada

  2. Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, IDIBAPS, Barcelona, Spain

    N Villamor, A López-Guillermo, A Martínez-Trillos & E Campo

  3. Centre de Regulació Genòmica and Universitat Pompeu Fabra, Barcelona, Spain

    J R Tejedor & J Valcárcel

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  1. A J Ramsay
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Ramsay, A., Rodríguez, D., Villamor, N. et al. Frequent somatic mutations in components of the RNA processing machinery in chronic lymphocytic leukemia. Leukemia 27, 1600–1603 (2013). https://doi.org/10.1038/leu.2012.344

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