miR-451a induced apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells by targeting IL-6R

Tao Jiang, Jiao Chen, Xiao-Bing Huang, Yan-Xing Li,  Ling Zhong

Abstract:

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is the most fatal leukemia due to the BCR/ABL fusion protein. This fusion protein can induce interleukin 6 (IL-6) expression in leukemia stem cells (LSCs) which sustain stemness by binding IL-6R and activating the Janus kinase (JAK)/signal transducer and activator of the transcription (STAT) pathway. IL-6R was one of the targets of miR-451a down-regulated in LSCs by BCR/ABL. We investigated the relationship between miR-451a, IL-6R, and BCR/ABL in Ph+ ALL and created a strategy to treat this disease. The expression levels of miR-451a and BCR/ABL of Ph+ ALL patients were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and serum IL-6 was tested by enzyme-linked immunosorbent assay. Ph+ ALL cell line SUP-B15 and Ph− ALL cell line Nalm-6 were treated with miR-451a mimic and inhibitor, respectively; proliferation rate was assessed by CCK-8, apoptosis rate was tested by Annexin/PI and the expression levels of Bcl-XL, Bax, cyclin D2 and c-myc were examined by qPCR and western blot (WB). The levels of STAT3, p-STAT3, JAK2, and p-JAK2 were tested by WB. We found that BCR/ABL was inversely related to miR-451a and positively related to IL-6 in Ph+ ALL. MiR-451a inhibited the proliferation of SUP-B15 through the apoptosis pathway. The oncogene c-myc was down-regulated by miR-451a. We confirmed that miR-451a could target IL-6R and inhibit activation of JAK and STAT3. In conclusion, miR-451a is down regulated in Ph+ ALL and increasing the expression levels of miR-451a in leukemia cells can increase the potential of curing this disease.