Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

Abstract

Recently, extracellular circulating microRNAs were also 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- 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. brane vesicles (exosomes from 50 to 100 nm and microvesicles from 100 nm to 1 μm) or protein/lipid complexes (8,9), since carrier-free microRNAs will be degraded by RNase digestion and other environmental factors (9). Their levels and composition have been shown to be modulated with injury conditions as well as tumor burden (10-12). For these reasons, extracellular microRNAs could be used as informative biomarkers to assess and monitor disease evolution (11,13). Moussay et al. (14) recently observed that some circulating microRNAs in CLL plasma could be used as prognostic factors. Among these, microRNA-150 warranted further investigation for a number of reasons. This microRNA plays an important role in normal and malignant hematopoiesis (15). In addition, plasma (14) and cellular (16,17) microRNA-150 were both downregulated in poor prognosis CLL patients based on ZAP70 and IgHV mutational status. A low level of cellular microRNA-150 was also observed in CLL proliferation centers (18), and microRNA-150 is differentially expressed according to the stereotyped B-cell receptor (BCR) subset taken into consideration (19), emphasizing its pivotal role in CLL. Finally, a recent s...

miR-150 Suppresses the Proliferation and Tumorigenicity of Leukemia Stem Cells by Targeting the Nanog Signaling Pathway

“…Accumulating data has demonstrated that miR-150 is associated with the development of lymphoid and myeloid lineages in human leukemia progression (He Y. et al, 2014; Stamatopoulos et al, 2015). However, the relationship between Nanog and miR-150 has not been elucidated.…”

“…In addition, in situ hybridisation revealed that the miR-150 expression level was decreased in breast cancer samples compared to adjacent normal cells (Huang et al, 2013). Reports by Stamatopoulos have revealed opposite prognostic significance for cellular and serum circulating miR-150 in CLL patients (Stamatopoulos et al, 2015). In our studies, we found that the miR-150 expression level was significantly decreased in CD34+ cells and LSCs compared with normal blood.…”

MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

“…MiR-150 is generally found to be downregulated in poor prognosis patients 32,33,38 , but Li and colleagues found that increased expression of miR-150 was associated with high expression of ZAP70 35 . In addition, a recent study found opposite prognostic significance of cellular and serum circulating miR-150 in CLL, where decreased levels of miR-150 in CLL B-cells, but increased levels of miR-150 plasma levels were associated with tumor burden, disease aggressiveness and poor prognostic factors, such as unmutated IGHV and increased expression of ZAP70, CD38 and B2M 39 .…”

mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients

“…Consequently, we support the notion that KLK14 mRNA expression merits further investigation in a larger cohort of CLL patients, as it seems to be a promising molecular prognostic biomarker in CLL. During the last decade, several new prognostic biomarkers have emerged, including expression of human leukocyte antigen (HLA-G) [50], high histone deacetylase (HDAC) activity [51], cellular and/or serum levels of miR-150 [52], as well as the aforementioned SOX1 [47] and soluble TACI [48]. Taking into account that all these suggested molecular biomarkers, including KLK14 mRNA expression, predict poor OS of CLL patients and that accumulation of several other adverse prognostic markers has been proven to worsen prognosis in CLL [53], it would be interesting to study their combinatorial prognostic value in this disease.…”