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   PMCID: PMC10429169
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   Background: The lncRNA CYTOR has been described to have oncogenic roles
   and its expression be associated with poor prognosis in several solid
   cancers. Nevertheless, its biological functions and clinical impact are
   still poorly known in lymphoid neoplasms. Particularly in CLL, there is
   only one report pointing to its overexpression measured by qRT-PCR in a
   subset of patients but lacking any significant clinical value in a
   series of Binet A CLL samples.

   Aims: To determine the prognostic value of the lncRNA CYTOR in a large
   series of well characterized CLL samples both clinically and
   biologically. Furthermore, we wished to characterize its potential
   biological roles in the CLL pathogenesis as well as the possible origin
   of its overexpression in a subset of patients.

   Methods: We analyzed CYTOR expression in RNA-seq data in CLL samples
   from the ICGC project ([41]https://dcc.icgc.org). In addition, CLL
   purified cells from 8 patients were treated ex vivo with some factors
   mimicking the microenvironment stimuli in the LN (CpG-ODN+CD40L+IL10)
   and compared with the corresponding untreated controls. From their
   purified total RNA, 10 ng were used for transcriptomic analysis with
   Clariom D WT pico microarray platform and TAC software (Applied
   Biosystems). Pathway enrichment analysis was performed using GSEA on
   ranked list of coding genes according to Pearson correlation of each
   gene from CYTOR levels across the series of samples.

   Results: CYTOR expression showed a significant association with a
   shorter time-to-treatment and overall survival, both in in Binet A
   cases as the entire cohort. Furthermore, this clinical impact was found
   to be independent of other well-established prognostic factors in CLL
   (IGHV mutational status and epigenetic subtypes as Binet stage) in
   multivariate Cox models. Biologically, CYTOR expression showed a
   significant positive correlation with the proliferative drive score
   previously described to be a poor prognostic marker in CLL, orthogonal
   to other known prognostic biomarkers and biologically associated with
   increased lymphocyte doubling rate and response to pro-proliferative
   stimuli (PMID: 34423310). Moreover, several pathways known to be
   related to CLL pathogenesis and proliferative drive were significantly
   enriched among coding genes correlated with CYTOR in the studied ICGC
   series, also including genes previously known to be upregulated in CLL
   cells in the lymph nodes compared to peripheral blood. Concordantly, we
   found its expression significantly increased in CLL cells treated ex
   vivo with some factors mimicking the microenvironment stimuli in the
   lymph nodes. The coding genes correlated with CYTOR in these samples
   also showed a highly significant enrichment in signatures previously
   described to be induced by CpG-ODN treatment.

   Summary/Conclusion: All these results showed that CYTOR has poor
   prognostic value in CLL and could be biologically related with the
   degree of microenvironment stimulation in the lymph nodes and the
   previously described proliferative drive in CLL.

   graphic file with name hs9-7-e4399183-g001.jpg
   [42]Open in a new tab

   Keywords: Hematological malignancy, B cell chronic lymphocytic
   leukemia, Prognostic factor
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   Articles from HemaSphere are provided here courtesy of Wiley
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