Downregulation of Plasma miR-215 in Chronic Myeloid Leukemia Patients with Successful Discontinuation of Imatinib

Abstract

Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients who were able to discontinue IM. We first screened candidate miRNAs in unselected STOP-IM patients, who had sustained UMRD after discontinuing IM for more than six months, in comparison with healthy volunteers, by using a TaqMan low-density array for plasma or exosomes. Exosomal miR-215 and plasma miR-215 were downregulated in the STOP-IM group compared to the control, indicating that the biological relevance of the plasma miR-215 level is equivalent to that of the exosomal level. Next, we performed real-time quantitative RT-PCR in 20 STOP-IM patients, 32 patients with UMRD on continued IM therapy (IM group) and 28 healthy volunteers. The plasma miRNA-215 level was significantly downregulated in the STOP-IM group (p < 0.0001); we determined the cut-off level and divided the IM group patients into two groups according to whether the plasma miR-215 was downregulated or not. The IM group patients with a low plasma miR-215 level had a significantly higher total IM intake, compared to the patients with elevated miR-215 levels (p = 0.0229). Functional annotation of miR-215 target genes estimated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools involved cell cycle, mitosis, DNA repair and cell cycle checkpoint. Our study suggests a possible role of miR-215 in successful IM discontinuation.

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

“…In this study, we present evidence that long-term exposure to IM, while leading to a significant downregulation of Bcr-Abl1 protein level and its activity, results in inactivation of the Hippo pathway kinase module and upregulation of YAP, and that these changes correlate with increased expression of stem cell markers and acquired insensitivity to IM. Our observations are in agreement with a recent report showing increased levels of miR-181a in the plasma of CML patients who discontinued IM (STOP-IM group) [30]. In the present studies, we have observed that inhibition of miR-181a resulted in a decrease in YAP levels, an increase in its phosphorylation, and a modest but statistically significant increase in sensitivity to IM.…”

“…We focused our subsequent studies on miR-181a as miR-181 family is the most highly conserved and the most preferentially expressed in the hematopoietic system [22,23]. To explore the association of miR-181a upregulation with long-term exposure to IM, we analyzed a published microarray data set: GEO GSE75392; seven CML patients from STOP-IM group and seven healthy volunteers [30]. We found that miR-181a was significantly upregulated in plasma isolated from CML STOP-IM group patients (Fig.…”

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

“…Exosomal miR-126 in endothelial cells modulates the adhesive and migratory abilities of CML cells [12]. Patients with a low plasma miR-215 expression had a significantly higher total imatinib intake compared to patients with increased miR-215 expression [13]. miR-21 was enriched in exosomes released by K562 and LAMA84 cells after treatment with curcumin, suggesting that selective packaging of miR-21 in the exosomes may contribute to the antileukemic effect of curcumin in CML [14].…”

Insight into the Leukemia Microenvironment and Cell-cell Interactions Using Flow Cytometry

“…Altogether, this supports the notion that leukemic EVs constitute an important mechanism of disease progression both by direct influence on CML cells and by indirect modification of leukemic niche components and immune cells. Moreover, EVs components, such as proteins and microRNAs, have recently become of interest as biomarkers in hematological malignancies [42,48,49]. Thus, analysis of EVs number, size, and composition may soon be used to diagnose, stage, and even analyze relapse of hematological malignancies in the clinical setting.…”