Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of res...Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.展开更多
Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable ...Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors （TKIs）, a significant proportion of CML patients treated with TKIs develop drug resis- tance due to the inability of TKIs to kill leukemia stem cells （LSCs） that are responsible for initiation, drug re- sistance, and relapse of CML. Therefore, there is an ur- gent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSC- associated targets and corresponding signaling path- ways, including CaMKII-y, a critical molecular switch for co-activating mu｜tipte LSC-associated signaling path- ways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and its- associated targets, and the potential clinical application in chronic myeloid leukemia.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.81370660,81170524)
文摘Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.
基金We apologize to the scientists who made contributions to the field, but have not been cited due to the space limitations. This work was sup- ported in part by the National Natural Science Foundation of China （Grant Nos. 81270601, 81328016, and 81470306） and Leukemia Research Innovative Team of Zhejiang Province （2011 R50015）.
文摘Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors （TKIs）, a significant proportion of CML patients treated with TKIs develop drug resis- tance due to the inability of TKIs to kill leukemia stem cells （LSCs） that are responsible for initiation, drug re- sistance, and relapse of CML. Therefore, there is an ur- gent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSC- associated targets and corresponding signaling path- ways, including CaMKII-y, a critical molecular switch for co-activating mu｜tipte LSC-associated signaling path- ways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and its- associated targets, and the potential clinical application in chronic myeloid leukemia.
