Small nucleolar RNA expression profiles refine the prognostic impact of IGHV mutational status on treatment‐free survival in chronic lymphocytic leukaemia

Abstract

. (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood, 117, 563-574. Hofbauer, S.W., Pinon, J.D., Brachtl, G., Haginger, L., Wang, W., Johrer, K., Tinhofer, I., Hartmann, T.N. & Greil, R. (2010) Small nucleolar RNA expression profiles refine the prognostic impact of IGHV mutational status on treatment-free survival in chronic lymphocytic leukaemiaChronic B-cell lymphocytic leukaemia (CLL) is generally an indolent disease, with most patients surviving years without treatment although some progress more rapidly. Several markers, such as IGHV mutational status (Hamblin et al, 1999), cytogenetic abnormalities (D€ ohner et al, 2000) and recurrent gene mutations (Wang et al, 2011;Jeromin et al, 2014), have helped to better stratify patient risk, but few are routinely used by clinicians and they are still relatively unreliable, reflecting the clinical and physiopathological heterogeneity of the disease. Thus there remains room for improvement and new molecular markers. Our understanding of the various roles of small nucleolar RNAs (snoRNAs) in cancer is continually expanding. Besides their well-known function in ribosomal RNA modifications, snoRNAs have recently been described as new biomarkers in haematological cancers (Ronchetti et al, 2012(Ronchetti et al, , 2013 Valleron et al, 2012a,b). Notably, Ronchetti et al (2013) studied a cohort of Binet stage A CLL patients, reporting that a specific snoRNA signature was predictive of outcome for early stage CLL. In this study, we investigated the snoRNA expression profiles in CLL patients fully annotated for both the classical prognostic markers (IGHV mutational status, cytogenetic abnormalities, Binet stage) and recurrent somatic mutations (TP53, NOTCH1, SF3B1). The methods and patient characteristics are described in Data S1, Tables SI and SII. Using high-throughput quantitative polymerase chain reaction (Fluidigm, Les Ullis, France), we first determined whether snoRNA profiling (n = 221, covering more than two-thirds of previously described snoRNAs) could discriminate between CLL prognostic subgroups in an exploration set of 58 treatment-naive CLL and five normal B-cells. Unsupervised hierarchical clustering showed that patients did not cluster together when considering criteria such as IGHV mutational status, Binet stage, age, gender, karyotype, fluorescence in situ hybridization and NOTCH1/ TP53/SF3B1mutation, but instead were scattered along the dendrogram (Fig S1). Supervised analysis also did not find a snoRNA signature specific to the conventional clinico-biological parameters, suggesting that snoRNA expression profiles were not associated with the aforementioned factors impacting on CLL outcome. The apparent contradiction between our results and those reported by Ronchetti et al (2013) could be explained by the differences between the two cohorts as we included more cases presenting adverse prognosis factors.However, the unsupervised analysis showed that...

Small Nucleolar RNAs: Insight Into Their Function in Cancer

“…Moreover, Valleron et al found that the overexpression of snoRNA HBI-239 and HBI-239-processed miRNA predicted good prognosis in angio-immunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (PTCL-NOS) (86). Berquet et al investigated the snoRNA expression profiles in B-cell chronic lymphocytic leukemia (CLL) patients and identified that immunoglobulin heavy chain variable region gene (IGHV)-mutant patients exhibiting overexpression of 20 snoRNAs had a shorter treatment-free survival (TFS) (87). SNORA70F and SNORD116-118 were developed into a 2-snoRNA model that appeared to distinguish two different prognostic CLL groups (88).…”

RNA-Seq profiling of deregulated miRs in CLL and their impact on clinical outcome

“…Induction of C/D box snoRNAs has been reported to favor leukemogenesis 44 . A number of snoRNAs have been reported to predict the clinical outcome in early stage as well as IGHV mutated CLL 45,46 . Various tRNA fragments have been reported to induce transient translational arrest 42 and tRNA derived small RNAs can function similarly to miRs.…”

Small nucleolar RNA is potential as a novel player in leukemogenesis and clinical application

“… 75 Furthermore, after CLL cells were induced to proliferate, 7 snoRNAs continued to be up-regulated with proliferation, while 2 snoRNAs (SNORA80 and SNORD1A) were down-regulated. 75 It is evident that snoRNAs are subject to complex regulation during the proliferation of CLL cells. Some snoRNAs may be deregulated during proliferation, whereas others may continue to be up-regulated, and the latter likely have important regulatory functions.…”