Downregulation of Plasma miR-215 in Chronic Myeloid Leukemia Patients with Successful Discontinuation of Imatinib.
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.
Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan. ohyashik@rr.iij4u.or.jp.|Department of Molecular Science, Tokyo Medical University, Tokyo 160-0023, Japan. ohyashik@rr.iij4u.or.jp.
Kazuma
K
Ohyashiki
Department of Molecular Science, Tokyo Medical University, Tokyo 160-0023, Japan. t_umezu@tokyo-med.ac.jp.
Tomohiro
T
Umezu
Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan. patchsei@yahoo.co.jp.
Seiichiro
S
Katagiri
Department of Molecular Science, Tokyo Medical University, Tokyo 160-0023, Japan. chiaki-k@tokyo-med.ac.jp.
Chiaki
C
Kobayashi
Department of Molecular Oncology, Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan. k_azuma@tokyo-med.ac.jp.
Kenko
K
Azuma
Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan. tauchi@tokyo-med.ac.jp.
Tetsuzo
T
Tauchi
Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan. okabe@tokyo-med.ac.jp.
Seiichi
S
Okabe
Department of Electrical Engineering, Kogakuin University, Tokyo 163-8677, Japan. fukuoka@cc.kogakuin.ac.jp.
Yutaka
Y
Fukuoka
Department of Molecular Oncology, Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan. junko@hh.iij4u.or.jp.
Junko H
JH
Ohyashiki
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*
D000970:Antineoplastic Agents; C553667:MIRN215 microRNA, human; D035683:MicroRNAs; D000068877:Imatinib Mesylate
chronic myeloid leukemia; discontinuation; imatinib; plasma miR-215