Radtke and colleagues investigated copy number alterations (CNAs) in pediatric AML genomes and found that the most common CNA is a low burden increase of a region within the CCDC26 locus. Despite the ambiguous nature of CCDC26, several lines of evidence support a relationship of CCDC26 with tumors, including AML. There is no evidence for a functional CCDC26 protein moreover, the hypothetical 109 amino acid protein encoded in its mRNA has no homology with known proteins. The function of the lncRNA, CCDC26, is not known. 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. KIT is a receptor tyrosine kinase that is considered to have a role in AML because of its frequent up-regulation in patients.
Considering the importance of imatinib, an ABL tyrosine kinase inhibitor used in the treatment of BCR/ABL-positive CML, inhibitors against other tyrosine kinases are likely to become increasingly important for the treatment of AML. Thus, hematopoietic tyrosine kinases, including FLT3, ABL, RAS and KIT, seem to have a similar role in AML and CML. However, acute blastic crisis of CML is often accompanied by mutation of genes that are also mutated in AML, such as HOXA9 or AML1. Fusion of BCR and ABL ( BCR/ ABL) is well known to be sufficient to cause chronic myeloid leukemia (CML). Mutations in genes of both classes need to occur to give rise to AML. One class includes genes related to cell differentiation, HOXA9, AML1, MLL and RARα, and the other consists of genes related to proliferation or survival of cells and includes FLT3, ABL, RAS and KIT. These genes can be divided into two classes. Accumulating evidence suggests that some lncRNAs are involved in diseases, such as cancer therefore, it is important to understand their roles to facilitate the search for new therapeutic targets and to design new diagnostic methods.Īcute myeloid leukemia (AML) is a disease characterized by mutations in a set of genes. However, apart from a few examples, the molecular mechanisms by which most lncRNAs function remain to be fully elucidated. MicroRNAs (miRNAs), are important ncRNAs of approximately 20 bp that silence specific target genes, while long noncoding RNAs (lncRNAs) are between 200 bp and several kb and have numerous roles in cellular functions and gene regulation. Noncoding RNAs (ncRNAs) are usually transcribed by RNA polymerase II and have intrinsic functions without being translated into polypeptides. A KIT inhibitor might be an effective treatment against the forms of AML in which CCDC26 is altered. We suggest that CCDC26 controls growth of myeloid leukemia cells through regulation of KIT expression. Treatment of KD clones with ISCK03, a KIT-specific inhibitor, eliminated the increased survival of KD clones in the absence of serum.
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. In contrast, enhanced growth rates in media containing much lower serum concentrations and increased survival periods after serum withdrawal were observed for KD clones. Growth rates of KD clones were reduced compared with non-KD control cells in media containing normal or high serum concentrations.
The shRNA targeting one of the two CCDC26 splice variants also suppressed the other splice variant, which is further evidence for TGS. 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. 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. We found that CCDC26 transcripts were abundant in the nuclear fraction of K562 human myeloid leukemia cells. The lncRNA, CCDC26, is related to childhood acute myeloid leukemia (AML) because its copy number is altered in AML patients. Accumulating evidence suggests that some long noncoding RNAs (lncRNAs) are involved in certain diseases, such as cancer.
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