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    The N-methyladenosine (mA)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Vu Ly P,Pickering Brian F,Cheng Yuanming,Zaccara Sara,Nguyen Diu,Minuesa Gerard,Chou Timothy,Chow Arthur,Saletore Yogesh,MacKay Matthew,Schulman Jessica,Famulare Christopher,Patel Minal,Klimek Virginia M,Garrett-Bakelman Francine E,Melnick Ari,Carroll Martin,Mason Christopher E,Jaffrey Samie R,Kharas Michael G Nature medicine N-methyladenosine (mA) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the mA modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the mA-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of mA coupled with ribosome profiling reveals that mA promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia. 10.1038/nm.4416
    Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation. Yu Zu-Yin,Xiao He,Wang Li-Mei,Shen Xing,Jing Yu,Wang Lin,Sun Wen-Feng,Zhang Yan-Feng,Cui Yu,Shan Ya-Jun,Zhou Wen-Bing,Xing Shuang,Xiong Guo-Lin,Liu Xiao-Lan,Dong Bo,Feng Jian-Nan,Wang Li-Sheng,Luo Qing-Liang,Zhao Qin-Shi,Cong Yu-Wen Cancer research All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR. 10.1158/0008-5472.CAN-15-1616
    4-Amino-2-Trifluoromethyl-Phenyl Retinate induced leukemia cell differentiation by decreasing eIF6. Wang Ke,Wang Cong,Zhu Chuan-Jun,Li Ge,Li Yue,Feng Yu-Bin,Ruan Jing-Jing,Zhu Fei,Meng Yao,Zhou Ren-Peng,Chen Fei-Hu Biochemical and biophysical research communications 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), an all-trans retinoic acid (ATRA) derivative, possesses the ability to relief several carcinoma. Here, we explored the potential molecular mechanism of eukaryotic translation initiation factor 6 (eIF6) in ATPR-induced leukemia cell differentiation. Our research showed that ATPR could inhibit cell proliferation and promote cell differentiation in several leukemia cell lines. Besides, ATPR remarkably reduced the expression of eIF6 in vitro. Interestingly, the reduction of eIF6 contributed to restraining proliferation of K562 cells by inhibiting CyclinD1, C-myc and blocking cell cycle, as well as promoting differentiation of K562 cells by increasing the expression of C/EBPε, cell surface antigen CD11b and inducing renal-shrinkage of nuclear. Furthermore, the over-expression of eIF6 restrained the effects of ATPR on cell proliferation and maturation in K562 cells. In Addition, Notch1/CBF-1 signal activated by Chrysin could increase expression of eIF6 and restrain the differentiation in ATPR-induced K562 cells. Taken together, all above results indicated that ATPR induced differentiation of leukemia cells by decreasing eIF6 through Notch1/CBF-1 signal, which might exert an innovative treatment for leukemia. 10.1016/j.bbrc.2018.07.153