C-kit is an oncogene that encodes a tyrosine kinase receptor called C-KIT (CD117). C-KIT is expressed in over 68% of Acute Myeloid Leukemia (AML) cells and it has been reported to play a crucial role in the pathogenesis of AML.1 Additionally, AML patients with C-KIT mutations often display drug resistance and inefficiency to clinical treatment. MicroRNAs (miRNA) have been reported to regulate C-KIT function. miR-137 has been shown to play a role in the pathogenesis of tumors, however, its precise role specifically in AML has not been elucidated yet.2
In an article published in Leukemia Research, Yanping Hu and colleagues from the Shengjing Hospital of China Medical University, PR China, discuss their findings from their study, which investigated the mechanism by which miR-137 regulates c-kit in AML samples.
The key results of the study were:
- miR-137 binds specifically to 3’ wtUTR but not mutUTR (contains four-nucleotide deletion in the miR-137 binding sites)
- Relative copy number of c-kit expression in healthy control and in patients with primary AML; 0.595 vs 2.450, P < 0.0001
- Relative copy number of c-kit expression in CD117+ cell lines and in CD117- cell lines; 10.36 vs 0.006, P = 0.3835
- Relative copy number of miR-137 expression in healthy control and in patients with primary AML; 6.531 vs 1.807, P = 0.0102
- Relative copy number of miR-137 expression in CD117+ cell lines and in CD117- cell lines; 0.628 vs 1.850, P = 0.0093
- Significant inverse linear correlation between c-kit and miR-137 expression in clinical AML samples and cell lines (CD117- and CD117+), r = -0.1801, P = 0.0373 and r = -0.900, P = 0.037, respectively
- Transfection of miR-137 to CD117+ cell lines, KASUMI-1 and K562 cells, decreased C-KIT protein levels, P =0.004 and P = 0.003
- Restoration of miR-137 inhibits the proliferation of KASUMI-1 and KD62 cells; P = 0.004 and P = 0.003
- Restoration of miR-137 increases apoptosis of KASUMI-1 and KD62 cells; P = 0.044 and P = 0.005
- Restoration of miR-137 increases the relative expression of CD15 KASUMI-1 and KD62 cells; P = 0.044 and P = 0.005
In summary, the results of this study show that a decrease in miR-137 level correlates with an increase in c-kit expression level in AML. Additionally, miR-137 targets the 3’UTR of c-kit and this leads to the downregulation of C-KIT protein levels. Furthermore, miR-137 can inhibit proliferation, and increase apoptosis and differentiation of AML cells, thus indicating that miR-137 downregulation of C-KIT plays a role in the pathogenesis of AML.
In conclusion, dysregulation of miR-137 can participate in the development of c-kit+ AML. The authors suggested that regulation of miR-137 expression can be an effective therapeutic strategy for patients with c-kit driven AML.
The oncogene c-kit plays a vital role in the pathogenesis of acute myeloid leukemia (AML). However, the mechanism of microRNAs targeting c-kit in AML has not been determined in detail. Moreover, the role miR-137 in tumor cell proliferation remains controversial. The aim of this work was to verify whether miR-137 targets c-kit and to research the biological effects of restoring miR-137 expression in leukemia cells. We found that miR-137 binds specifically to the 3′-UTR of c-kit and suppresses the expression and activities of c-kit. There is a negative correlation between miR-137 and c-kit expression in both patients and cell lines determined by screening large clinical samples. We found that miR-137 can inhibit proliferation, promote apoptosis, and induce differentiation of c-kit+ AML cells. We determined that miR-137 can participate in the leukemogenesis by regulating c-kit, which could be used as a therapeutic target for acute myeloid leukemia.