Abstract
BackgroundAccumulating evidence suggests that some long noncoding RNAs (lncRNAs) are involved in certain diseases, such as cancer. The lncRNA, CCDC26, is related to childhood acute myeloid leukemia (AML) because its copy number is altered in AML patients.ResultsWe found that CCDC26 transcripts were abundant in the nuclear fraction of K562 human myeloid leukemia cells. To examine the function of CCDC26, gene knockdown (KD) was performed using short hairpin RNAs (shRNAs), and four KD clones, in which CCDC26 expression was suppressed to 1% of its normal level, were isolated. This down-regulation included suppression of CCDC26 intron-containing transcripts (the CCDC26 precursor mRNA), indicating that transcriptional gene suppression (TGS), not post-transcriptional suppression, was occurring. The shRNA targeting one of the two CCDC26 splice variants also suppressed the other splice variant, which is further evidence for TGS. Growth rates of KD clones were reduced compared with non-KD control cells in media containing normal or high serum concentrations. In contrast, enhanced growth rates in media containing much lower serum concentrations and increased survival periods after serum withdrawal were observed for KD clones. DNA microarray and quantitative polymerase chain reaction screening for differentially expressed genes between KD clones and non-KD control cells revealed significant up-regulation of the tyrosine kinase receptor, KIT, hyperactive mutations of which are often found in AML. Treatment of KD clones with ISCK03, a KIT-specific inhibitor, eliminated the increased survival of KD clones in the absence of serum.ConclusionsWe suggest that CCDC26 controls growth of myeloid leukemia cells through regulation of KIT expression. A KIT inhibitor might be an effective treatment against the forms of AML in which CCDC26 is altered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0364-7) contains supplementary material, which is available to authorized users.
Highlights
Accumulating evidence suggests that some long noncoding RNAs are involved in certain diseases, such as cancer
Considering the importance of imatinib, an ABL tyrosine kinase inhibitor used in the treatment of BCR/ABLpositive chronic myeloid leukemia (CML), inhibitors against other tyrosine kinases are likely to become increasingly important for the treatment of acute myeloid leukemia (AML) [19,23]
Expression of CCDC26 in various leukemia cell lines To investigate the spectrum of cells that express CCDC26, the absolute number of RNA molecules in a cell was determined by quantitative polymerase chain reaction (PCR) in several representative leukemia and non-leukemia cancer cell lines
Summary
Accumulating evidence suggests that some long noncoding RNAs (lncRNAs) are involved in certain diseases, such as cancer. MicroRNAs (miRNAs), are important ncRNAs of approximately 20 bp that silence specific target genes [5,6,7,8,9], while long noncoding RNAs (lncRNAs) are between 200 bp and several kb and have numerous roles in cellular functions. Acute myeloid leukemia (AML) is a disease characterized by mutations in a set of genes [15,16,17]. These genes can be divided into two classes. Hematopoietic tyrosine kinases, including FLT3, ABL, RAS and KIT, seem to have a similar role in AML and CML [22]. Expression of KIT in leukemia stem cells (LSCs) from pediatric AML patients who relapsed after chemotherapy was increased compared with that in patients who did not relapse [24]
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