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.
Highlights
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), are a standard frontline therapy for chronic myeloid leukemia (CML) that yields successful outcomes [1]
We have reported that extracellular microRNAs, including plasma miRNAs and exosomal miRNAs, are altered in hematopoietic neoplasias [7,8,9], and some support malignant progression via the microenvironment [10,11]. miRNAs are noncoding single-stranded RNAs of 21–25 nucleotides that have recently been implicated in the regulation of cellular processes, such as apoptosis, proliferation, development or differentiation, in normal hematopoiesis, and in hematological malignancies
Since the total IM intake dose was significantly higher in CML patients with low miR-215 levels in the IM group, CML stem cells may be more suppressed, the prognosis in the CML-IM group did not differ between patients with and without low plasma miR-215 expression
Summary
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), are a standard frontline therapy for chronic myeloid leukemia (CML) that yields successful outcomes [1]. In the STIM study, approximately 40% of CML patients with a molecular remission of at least a two years’ duration safely discontinued IM; they maintained undetermined minimal residual disease (UMRD) for more than two years, and 60% maintained major molecular response (MMR: MR4.0) [3]. The STIM study showed that male gender, low Sokal score and IM duration of >72 months were associated with maintaining treatment-free remission [3]. Reduction of BCR-ABL1 transcription by TKIs induces a deep molecular response [5], and expansion of cytotoxic natural killer (NK) cells [6] could serve as a predictive marker for future treatment-free remission. The cellular component is obtained in the context of leukemia; analysis of the cell-free fraction, including plasma, is worthwhile in cases of complete remission when neoplastic cells are not present in the peripheral blood. We attempted to identify circulating miRNAs in CML patients who maintained UMRD after stopping IM (STOP-IM), and we studied target molecules by using bioinformatics tools
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