Abstract
MicroRNAs (or miRs) play a crucial role in chronic lymphocytic leukemia (CLL) physiopathology and prognosis. In addition, circulating microRNAs in body fluids have been proposed as new biomarkers. We investigated the expression of matched cellular and serum circulating microRNA-150 by quantitative real-time PCR (qPCR) from purified CD19(+) cells or from CLL serums obtained at diagnosis in a cohort of 273/252 CLL patients with a median follow-up of 78 months (range 7-380) and correlated it to other biological or clinical parameters. We showed that miR-150 was significantly overexpressed in CLL cells/serums compared with healthy subjects (P < 0.0001). Among CLL patients, a low cellular miR-150 expression level was associated with tumor burden, disease aggressiveness and poor prognostic factors. In contrast, a high level of serum miR-150 was associated with tumor burden markers and some markers of poor prognosis. Similarly, cellular and serum miR-150 also predicted treatment-free survival (TFS) and overall survival (OS) in an opposite manner: patients with low cellular/serum miR-150 levels have median TFS of 40/111 months compared with high-level patients who have a median TFS of 122/60 months (P < 0.0001/P = 0.0066). Similar results were observed for OS. We also found that cellular and serum miR-150 levels vary in an opposite manner during disease progression and that cellular miR-150 could be regulated by its release into the extracellular space. Cellular and serum levels of miR-150 are associated with opposite clinical prognoses and could be used to molecularly monitor disease evolution as a new prognostic factor in CLL.
Highlights
Chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is characterized by the accumulation of a subtype of CD5+ B lymphocytes in blood, lymph nodes and bone marrow [1]
These different prognoses can be predicted by several prognostic factors, including clinical markers, such as Binet stage classification; molecular markers, such as mutational status of immunoglobulin heavy-chain variable region (IgHV) and its surrogate markers, ζ-associated protein-70 (ZAP70) and lipoprotein lipase (LPL); serum markers, including β2-microglobulin (β2-M) or soluble CD23; proliferation markers, such as lymphocyte doubling time (LDT); cytogenetic markers; and surface
Similar results were obtained for several classic poor prognostic markers commonly used to prognosticate CLL evolution (IgHV mutational status, ZAP70, LPL and CD38 expression, and cytogenetic abnormalities) (Supplementary Table S1 and Figure 2)
Summary
Chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is characterized by the accumulation of a subtype of CD5+ B lymphocytes in blood, lymph nodes and bone marrow [1]. MicroRNAs (miR) are small, noncoding RNAs of ~22 nucleotides that can regulate gene expression by hybridizing with a target mRNA sequence, resulting in translational repression or message degradation [5]. For all of these reasons, microRNAs have been considered a new class of tumor suppressors [6]. Extracellular circulating microRNAs were detected in body fluids, such as serum, plasma, saliva and urine [7]. These circulating microRNAs are believed to be chaperoned by various carriers, such as secreted mem-
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