Abstract
We have used polysome profiling coupled to microarray analysis to examine the translatome of a panel of peripheral blood (PB) B cells isolated from 34 chronic lymphocytic leukaemia (CLL) patients. We have identified a ‘ribosome-related' signature in CLL patients with mRNAs encoding for ribosomal proteins and factors that modify ribosomal RNA, e.g. DKC1 (which encodes dyskerin, a pseudouridine synthase), showing reduced polysomal association and decreased expression of the corresponding proteins. Our data suggest a general impact of dyskerin dysregulation on the translational apparatus in CLL and importantly patients with low dyskerin levels have a significantly shorter period of overall survival following treatment. Thus, translational dysregulation of dyskerin could constitute a mechanism by which the CLL PB B cells acquire an aggressive phenotype and thus have a major role in oncogenesis.
Highlights
Chronic lymphocytic leukaemia (CLL) has an extremely variable outcome with overall survival (OS) ranging from months to decades; some patients require immediate treatment upon diagnosis, whereas others remain asymptomatic for the whole course of the disease
Somatic mutations have been identified in ribosomal proteins in cancers, and mutations in ribosomal protein large (RPL)-5 and RPL11 have been found in patients with T-cell acute lymphoblastic leukaemia (T-ALL),[19] and in RPL10 and RPL22 in gastric and ovarian cancers,[20,21] and RPL15 and RPS15 have been identified recently as mutated in a subset of CLL patients.[22,23]
To study the translational status of peripheral blood (PB) CLL purified B cells isolated from patient samples, polysome profiling on cDNA microarrays was performed and the data compared with control B cells (CD45+, CD19+ and CD3 − ) obtained using CD20+ selection
Summary
CLL has an extremely variable outcome with overall survival (OS) ranging from months to decades; some patients require immediate treatment upon diagnosis, whereas others remain asymptomatic for the whole course of the disease. Our data show that there is a ribosome-related signature in a PB CLL B-cells with reduced polysomal association and expression of ribosomal proteins, and factors that modify ribosomal rRNA, including DKC1 that encodes for the highly conserved nucleolar protein dyskerin. The latter protein associates with the H/ACA class of small nucleolar RNAs and functions as a pseudouridine synthase, converting uridine to pseudouridine residues in ribosomal RNA (rRNA) during ribosomal maturation in the nucleolus. We show that DKC1 protein expression is a prognostic factor correlating with poor OS following treatment
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