Genetic subclonal complexity and miR125a-5p down-regulation identify a subset of patients with inferior outcome in low-risk CLL patients
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Gian Matteo Rigolin1, Elena Saccenti1,2, Lara Rizzotto1, Manuela Ferracin2, Sara Martinelli1, Luca Formigaro1, Francesca Cibien1, Maurizio Cavallari1, Enrico Lista1, Giulia Daghia1, Olga Sofritti1, Maria Ciccone1, Francesco Cavazzini1, Laura Lupini2, Cristian Bassi2, Barbara Zagatti2, Massimo Negrini2, Antonio Cuneo1
1 Hematology Section, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale S. Anna, Ferrara, Italy
2 Laboratory for Technologies of Advanced Therapies (LTTA) and Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
Gian Matteo Rigolin, email:
Keywords: Oncotargets, miR-125a-5p, CLL, CD38, prognosis
Received: September 8, 2013 Accepted: October 28, 2013 Published: October 30, 2013
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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