MiR-181 family: regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets
| Autor: | Jia-Nan Gong, Xiang Zhang, Jie Chen, Fang Wang, Liu B, Li Song, Hua-Lu Zhao, Jiao-jiao Yu, Haishuang Lin, Rui Su, Yin Xl, Chao Shen, Jun-Wu Zhang, Yanni Ma, Zhai Pf, Ning Hm |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Myeloid Cellular differentiation CD34 Calcium-Calmodulin-Dependent Protein Kinase Kinase HL-60 Cells Tretinoin Biology Mice Transduction Genetic hemic and lymphatic diseases Genetics medicine Animals Humans Myeloid Cells Molecular Targeted Therapy RNA Messenger Molecular Biology Base Sequence Macrophages Tumor Suppressor Proteins Myeloid leukemia Cell Differentiation medicine.disease Hematopoietic Stem Cells Rats Gene Expression Regulation Neoplastic Haematopoiesis Leukemia Leukemia Myeloid Acute MicroRNAs Protein Kinase C-delta PRKCD medicine.anatomical_structure Immunology Cancer research CCAAT-Enhancer-Binding Proteins Tetradecanoylphorbol Acetate Cattle Bone marrow Granulocytes Signal Transduction |
| Zdroj: | Oncogene. 34(25) |
| ISSN: | 1476-5594 |
| Popis: | MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy. |
| Databáze: | OpenAIRE |
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