title: Genetic subclonal complexity and miR125a-5p down-regulation identify a subset of patients with inferior outcome in low-risk CLL patients.
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.
authors: Hematology Section, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale S. Anna, Ferrara, Italy.
authors: Gian Matteo
authors: GM
authors: Rigolin
authors: Elena
authors: E
authors: Saccenti
authors: Lara
authors: L
authors: Rizzotto
authors: Manuela
authors: M
authors: Ferracin
authors: Sara
authors: S
authors: Martinelli
authors: Luca
authors: L
authors: Formigaro
authors: Francesca
authors: F
authors: Cibien
authors: Maurizio
authors: M
authors: Cavallari
authors: Enrico
authors: E
authors: Lista
authors: Giulia
authors: G
authors: Daghia
authors: Olga
authors: O
authors: Sofritti
authors: Maria
authors: M
authors: Ciccone
authors: Francesco
authors: F
authors: Cavazzini
authors: Laura
authors: L
authors: Lupini
authors: Cristian
authors: C
authors: Bassi
authors: Barbara
authors: B
authors: Zagatti
authors: Massimo
authors: M
authors: Negrini
authors: Antonio
authors: A
authors: Cuneo
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D006801:Humans; D018189:Immunomagnetic Separation; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D035683:MicroRNAs; D051997:ADP-ribosyl Cyclase 1