p18^(INK4C)缺失通过激活LMO2加快Notch-1诱导的急性T淋巴细胞白血病进展  

Loss of CDKN2C accelerates progression of Notch-1 induced T lymphoblastic leukemia via activation of LMO2

作　　者：董芳 拜海涛 王晓芳 张森 张珊珊 马士卉 Hideo Ema 程涛 郝莎 DONG Fang;BAI HaiTao;WANG XiaoFang;ZHANG Sen;ZHANG ShanShan;MA ShiHui;EMA Hideo;CHENG Tao;HAO Sha(State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin 300020, China;Department of Stem Cell ＆ Regenerative Medicine, Peking Union Medical College, Tianjin 300020, China)

机构地区：[1]中国医学科学院&北京协和医学院血液病医院(血液学研究所),实验血液学国家重点实验室,天津300020 [2]中国医学科学院干细胞医学中心,天津300020 [3]北京协和医学院干细胞与再生医学系,天津300020

出　　处：《中国科学：生命科学》2017年第12期1386-1396,共11页Scientia Sinica(Vitae)

基　　金：国家自然科学基金(批准号:81500085,81670106,81470279,81670105,81421002,81730006);中国医学科学院&北京协和医学院协和青年科研基金项目(批准号:3332015127)资助

摘　　要：p18^(INK4C)(CDKN2C)属于细胞周期蛋白激酶抑制剂家族成员,通过阻断细胞周期蛋白激酶4/6使细胞周期处于G1早期.研究提示,p18缺失影响T细胞的正常发育并可能参与急性T淋巴细胞白血病(T-ALL)的发生,但p18缺失导致T-ALL发生和进展的机制并不清楚.本文利用Notch-1胞内段(ICN-1)过表达诱导的T-ALL模型来研究p18影响T-ALL的发生和进展的可能机制.结果发现,p18-/-骨髓细胞过表达ICN-1可诱发T-ALL,白血病细胞表型为更加原始的CD4/CD8双阴性细胞,且这些细胞主要阻滞在DN3阶段;T-ALL细胞连续移植结果显示,p18缺失能够显著加速T-ALL的进展,且p18-/-T-ALL细胞更多地处于细胞周期的G0期,即静息状态;基因表达结果发现,与T-ALL发生直接相关的原癌基因Lmo2及共结合分子如Sfpi1,Nfe2及Ldb1等以及N-myc的表达水平在p18-/-组显著高于对照组.以上结果提示,p18缺失后可能通过激活Lmo2及N-myc等的表达从而加速T-ALL的进展.本研究对p18缺失如何加速T-ALL的发展进行了阐释,对临床伴随有p18缺失或者LMO2异常激活型突变T-ALL病人的预后提供了理论依据,具有一定的临床指导价值.The cyclin-dependent kinases inhibitor CDKN2 C（p18 INK4 C, p18） is a member of the INK4 family that specifically blocks the activity of CDK4/6 in the G1 phase of cell cycle. In the hematopoietic system, deletion of p18 is associated with T cell malignancies in mice and B cell malignancies in humans. The mice reconstituted with p18 knockout（ko） bone marrow（BM） cells spontaneously developed acute T lymphoblastic leukemia（T-ALL） in serial transplantation（2 years after transplantation） originating from a CD3 lowcell population. However, how p18 is involved in the development of T-ALL leukemia is largely unknown. In this study, Intercellular domain of Notch1（ICN-1） induced T-ALL model was used to explore the role of p18 deficiency in the development of T-ALL leukemia. Both hematopoietic stem and progenitor LSK（Lin-c-Kit＋Sca-1＋） cells transduced with ICN1-GFP retrovirus from p18＋/＋or p18-/-mice initiated the T-ALL. The majority of CD3＋cells were CD4/8 double positive in p18＋/＋group while that of CD3＋cells were CD4/8 double negative in p18-/-group. The serial transplantation of T-ALL cells showed accelerated progression of leukemia in p18-/-group compared with the p18＋/＋group in first, secondary and tertiary transplantation（P=0.01, P0.001, P0.001 respectively）.The Brd U assay suggested an increased proportion of G0 phase cells and decreased proportion of G1 phase in p18-/-group compared with p18＋/＋group. The gene expression analysis also showed higher expression of Lmo2 and N-myc in the leukemia cells of p18-/-group compared with p18＋/＋group. Deletion of p18 activates the expression of Lmo2 and N-myc although a mechanism is yet to be further defined. Taken together, our current study provides evidence and mechanism insights for the role of p18 deficiency during progression of T-ALL.

关 键 词：细胞周期蛋白激酶抑制剂 p18INK4C 急性T淋巴细胞白血病 LMO2 

分 类 号：R733.71[医药卫生—肿瘤]