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. 2014 Jan 15;5(1):140-9.
doi: 10.18632/oncotarget.1382.

Genetic subclonal complexity and miR125a-5p down-regulation identify a subset of patients with inferior outcome in low-risk CLL patients

Gian Matteo Rigolin  1 , Elena Saccenti, Lara Rizzotto, Manuela Ferracin, Sara Martinelli, Luca Formigaro, Francesca Cibien, Maurizio Cavallari, Enrico Lista, Giulia Daghia, Olga Sofritti, Maria Ciccone, Francesco Cavazzini, Laura Lupini, Cristian Bassi, Barbara Zagatti, Massimo Negrini, Antonio Cuneo
Affiliations

Genetic subclonal complexity and miR125a-5p down-regulation identify a subset of patients with inferior outcome in low-risk CLL patients

Gian Matteo Rigolin et al. Oncotarget. .

Abstract

The majority of patients with chronic lymphocytic leukemia (CLL) and favorable prognostic features live for long periods without treatment. However, unexpected disease progression is observed in some cases. In a cohort of untreated CD38- CLL patients with normal FISH or isolated 13q- we found that, by fluorescence in situ hybridization (FISH), 16/28 cases presented, within immunomagnetic sorted CD38+ cells, genetic lesions undetectable in the CD38- fraction. These patients showed a shorter time to first treatment (TTFT, p=0.0162) in comparison to cases without FISH lesions in CD38+ cells. Patients with FISH abnormalities in CD38+ cells showed a distinctive microRNA profile, characterized by the down-regulation of miR-125a-5p both in the CD38- and CD38+ populations. In an independent cohort of 71 consecutive untreated CD38- CLL with normal FISH or isolated 13q-, a lower miR125a-5p expression was associated with a shorter TTFT both in univariate and multivariate analysis (p=0.003 and 0.016, respectively) and with a higher prevalence of mutations (7/12 vs 0/8, p=0.015) as assessed by next-generation sequencing. In conclusion, our data showed previously unrecognized subclonal heterogeneity within the CD38+ fraction of CD38- CLL patients with low-risk FISH findings and suggested an association between down-regulated miR-125a-5p expression, genetic complexity and worse outcome.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Cluster analysis of patients with (W) and without (WO) lesions in the CD38+ fraction
miRNA profiling of CD38+ (a) and CD38- (b) cells from CD38- CLL patients with (red) and without (blue) FISH lesions in the CD38+ fraction. A distinctive miRNA profile characterized patients with and without FISH lesions both in the CD38+ (23 microRNAs) and CD38- cells (9 microRNAs). The colors of the genes represented on the heatmap correspond to the expression values normalized on miRNA mean expression across all samples: green indicates down-regulated; red indicates up-regulated.
Figure 2
Figure 2. Time to first treatment in cohort 1 (A) and cohort 2 (B) respectively, according to the presence (W) or not (WO) of FISH lesions in CD38+ cells and to the level of expression of miR125a-5p (low or high), respectively
See this image and copyright information in PMC

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