| Autor: |
Tian C; Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China., You MJ; Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Yu Y; Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China., Zhu L; Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China., Zheng G; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, People's Republic of China. zhenggg@ihcams.ac.cn., Zhang Y; Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China. yizhuozhang111@163.com. |
| Abstrakt: |
Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies sustained by leukemic stem cells (LSCs) that can resist treatment. Previously, we found that low expression of Hes1 was a poor prognostic factor for AML. However, the activation status of Hes1 and its regulation in LSCs and leukemic progenitors (LPs) as well as normal hematopoietic stem cells (HSCs) in Hes1-low AML patients have not been elucidated. In this study, the expression of Hes1 in LSCs and LPs was analyzed in adult CD34(+) Hes1-low AML with normal karyotype and the upstream microRNA (miRNA) regulators were screened. Our results showed that the level of either Hes1 or p21 was lower in LSCs or LPs than in HSCs whereas the level of miR-9 was highest in LPs and lowest in HSCs. An inverse correlation was observed in the expression of Hes1 and miR-9. Furthermore, we validated miR-9 as one of the regulators of Hes1 by reporter gene analysis. Knockdown of miR-9 by lentivirus infection suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro. Moreover, knockdown of miR-9 resulted in decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model. Our results indicate that the miR-9 plays an important role in supporting AML cell growth and survival by downregulation of Hes1 and that miR-9 has potential as a therapeutic target for treating AML. |
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