以LSC为靶标的复方浙贝颗粒抗AML临床研究
|
摘要
本文由两部分组成,通过两篇文献综述回顾了白血病干细胞(leukemia stem cell,LSC)具有自我更新和无限增殖潜能,是造成白血病发生发展的根源。而且LSC处于静止期,对化疗药物不敏感,易产生对多种化疗药物的交叉耐药,一般细胞周期化疗药物很难对其发挥杀伤效果。加之LSC集中于药物难以达到的骨髓区域以及具有天然耐药特性,正好逃逸了抗癌药物的攻击,为急性白血病复发潜伏了祸根。当多数白血病患者处于临床完全缓解状态时,体内仍残留包括LSC在内的微小残留病灶会重新活跃进入细胞分裂周期,并很快自我更新,无限增殖,造成急性白血病复发。临床观察还发现,部分难治性急性白血病患者一旦使用化疗既会出现严重的骨髓抑制,但停药后外周血或骨髓却很快显现大量的白血病细胞,且具有耐药相关蛋白高表达特征,支持LSC具有高度增殖潜能与多药耐药的生物学特征。因此针对LSC源头上的靶向干预治疗是克服白血病多药耐药最有效途径。我们前期研究发现,复方浙贝颗粒联合化疗能够提高难治性急性白血病患者临床缓解率,效应机制与诱导细胞凋亡、降低膜耐药蛋白高表达、调节酶异常变化相关,但均以白血病细胞为靶标,是否能针对LSC起到逆转耐药效应缺乏深入研究。临床研究主要为：
1.研究目的
通过观察复方浙贝颗粒联合化疗对难治性急性髓系白血病(acute myeloid leukemia, AML)患者骨髓LSC表面分子标志物的影响及难治性AML患者白血病细胞PI3K/Akt/mTOR信号通路和NF-κB信号通路中相关分子标记物(PI3K、mTOR、PTEN、 NF-κB)与骨髓周围微环境相互作用的细胞表面标记物CD44表达变化,试图明确复方浙贝颗粒逆转多药耐药效应靶点。
2.研究方法
全部病例资料来自北京中医药大学东直门医院血液肿瘤科,北京大学人民医院血液科,廊坊市中医医院血液科于2011年12月至2013年8月观察的难治性AML患者。治疗采用化疗方案有HAE, MA, CAG, AA, EA, FLAG等,复方浙贝颗粒(浙贝母12克,川芎9克,防已9克)由北京康仁堂药业有限公司制成中药配方颗粒,于化疗前3天开始服用复方浙贝颗粒,每次1袋,每日2次,共服用14天,21天为一疗程。以流式细胞术分别检测骨髓有核细胞中LSC表面分子标志物(CD34+CD123+、 CD33+CD123+)细胞表达比例。有30例患者完成治疗前后对照,分别检测了2次LSC表达比例；另外23例患者仅检测了1次LSC表达比例。20例次在北京中医药大学东直门医院血液肿瘤科住院的难治性AML患者行骨髓活检术采集组织标本,以免疫组化技术检测了CD44、PI3K、mTOR、PTEN、NF-κB表达情况。
3.研究结果
①难治AML中CD34+与CD33+CD123+细胞比例分别为11.78%、12.86%,两者相关性分析显示相关系数为0.953,两者具有明显相关性(p<0.001)。②按诊疗标准分类将难治性AML分为两组,其中处于缓解状态时患者的LSC表达比例分别为0.66%,0.92%,较处于复发状态时LSC比例(20.73%,22.47%)明显降低,差异具有统计学意义(p<0.001)。
③30例完成前后治疗对照的难治性AML患者治疗后LSC表面分子标志物细胞表达比例(5.49%,5.94%)较治疗前明显降低(17.05%,17.71%),差异有统计学意义(p<0.05)。其中25例处于复发状态时完成治疗前后对照的患者进一步分析发现,治疗后LSC比例(6.82%,7.39%)也较治疗前LSC比例(21.74%,22.48%)明显降低,差异有统计学意义(p<0.01)。治疗后达到完全缓解有10例患者(有效率40%),且LSC表面分子标志物细胞表达比例分别为1.50%,1.65%,较未缓解患者明显下降(11.65%,12.61%),差异具有统计学意义(p<0.01)。
④20例取骨髓活检患者中9例处于完全缓解的白血病细胞相关分子标记物CD44、PI3K、mTOR.PTEN.NF-κB阳性细胞表达率分别为22.2%、0%、33.3%、33.3%、77.8%,与11例未缓解的63.6%、0%、18.2%、63.6%、90.9%相比,CD44表达差异有统计学意义(p<0.05),阳性表达强度也提示CD44表达在两组间有统计学差异。完全缓解的白血病细胞相关分子标记物CD44.PI3K.mTOR.PTEN.NFκB平均光密度分别为441.78、217.28、393.58、91.16、642.66,与未缓解的840.06、316.21、223.00、292.51、775.35相比,CD44表达差异有统计学意义(p<0.05)。
4.研究结论
①CD34'CD123+与CD33+CD123+细胞具有显著相关,可以用来定位LSC。
②LSC比例可以反映急性白血病患者是否处于持续缓解状态。
③复方浙贝颗粒是通过降低LSC表面分子标记物CD123、CD33表达比例,提高了难治性AML化疗缓解率。
④白血病细胞中CD44高表达可作为难治性AML预后判定的重要参考指标,PI3K/Akt/mTOR信号通路和NF-κB信号通路在白血病细胞中的作用需要进一步研究。
This article contains two parts. From literature review, leukemia stem cell (LSC) which has self renewal capacity and infinite proliferation potential is the root of acute leukemia. LSC is in stationary stage, reluctant to most chemotherapy drugs, and easily causes multidrug resistance in leukemia cells. LSC concentrates in bone marrow niche where chemotherapy drugs can't reach and owns natural resistance characteristics, so LSC can avoid drug's attack to be a risk factor of relapsed acute leukemia. When most acute leukemia patients are in clinical complete remission stage, minimal residual diseases including LSC could repeatedly activate into cell cycles, realize self renewal and infinitely proliferated, then acute leukemia patients will become relapsed. In clinical observation, some refractory acute leukemia patients turn out to serious myelosuppression after chemotherapy, but they will relapse quickly with mass leukemia cells possessing over expression of drug-resistant related proteins in peripheral blood or bone marrow after drugs withdrawl. This indicates that LSC has biological characteristics of high proferation potential and multidrug resistance. Targeting on leukemia stem cell may be one of best therapies to overcome leukemia cells'multidrug resistance. In previous studies, Compound Zhebei Granule plus chemotherapy can improve clinical efficacy of refractory acute leukemia, which curative mechanisms rely on inducing cell apoptosis, down regulating over expression resistant proteins on membrane surface and adjusting abnormal changes of enzymes about multidrug resistance. These studies focus on leukemia cells and lack further researching on its function of leukemia stem cell.
Objective: this thesis is to investigate the efficacy of Compound Zhebei Granule plus chemotherapy on acute myeloid LSC's surface markers, and to detect the expression of PI3K/Akt/mTOR and NF-κB signal pathway biomarkers (PTEN, PI3K, mTOR, NF-κB) and bone marrow peripheral microenviroment' scell surface marker (CD44) related with bone marrow cells in patients with refractory acute myeloid leukemia.
Methods:From December,2011to August,2013, all cases who were candidates for refractory acute myeloid leukemia criteria were included from department of oncology and hematology in Dongzhimen hospital affiliated Beijing University of Traditional Chinese Medicine, department of hematology in Renmin hospital affiliated Beijing University and department of hematology in Langfang hospital of Chinese medicine. The common chemotherapy has HAE, MA, CAG, AA, EA, FLAG, et al. Compound Zhebei Granules are composed of fritillaria12grams,ligust icum9grams and tetrandr ine9grams, and is made into granule by Beijing tcmages pharmaceutical company limited. Compound Zhebei Granules were taken before chemotherapy in three days, once one bag, and twice a day, lasting fourteen days, twenty-one days a treatment cycle. Two milliliters bone marrow were analyzed by flow cytometry to evaluate the quantity of CD34+CD123+、CD33+CD123+leukemia stem cell. Thirty patients had undergone Compound Zhebei Granules plus chemotherapy and were abstracted bone marrow twice, the other twenty three patients were abstracted bone marrow once. Twenty patients in department of oncology and hematology in Dongzhimen hospital affiliated Beijing University of Traditional Chinese Medicine have abstracted bone marrow biopsy, then to do immunohis tochemistry to detect PTEN, PI3K, mTOR, NF-κB and CD44in all the samples. Results:①The proportions of CD34+CD123+, CD33+CD123+cells in refractory AML respectively are11.78%,12.86%, the correlation coefficient between them is0.953, both of them have significant correlation (p<0.001).
②Eighty-three cases of refractory acute leukemia had been tested the proportions of CD34+CD123+, CD33+CD123+cel Is. According to diagnostic criteria and therapeutic standards, the proportions of LSC in refractory AML patients who were under remission stations are0.66%,0.92%, which have a significant decrease when compared with the proportions of leukemia stem cell in refractory AML patients who were under relapsed stations.
③Thirty refractory AML patients had gone through Compound Zhebei Granules plus chemotherapy. Compared with the prior chemotherapy group (17.05%,17.71%), the proportions of LSC cells in post-treatment group (5.49%,5.94%) have a significant decrease (p<0.05). To further investigation, the proportions of leukemia stem cell in twenty-five patients who were under relapsed stations also had a significant decrease when compared with the prior chemotherapy group. Ten patients in twenty-five who were refractory AML patients under relapsed stations had accomplished completely release with the effects of Compound Zhebei Granules plus chemotherapy, and the remission rate is40%. When compared with the unreleased group, the proportions of CD34+CD123+, CD33+CD123+cel Is have a statistical significant reduction (p<0.01)in clinical remission.
④Twenty refractory AML pat ients who have biopsy bone marrow were divided into nine patients who were in remission stations and eleven patients who were unreleased stations. The positive expression rates of PTEN, mTOR, NF- kB, CD44and PI3K in nine remission patients were33.3%,33.3%,77.8%,22.2%and0%, meanwhile in eleven relapsed patients, the positive expression rates were63.6%,18.2%,90.9%,63.6%and0%. There were statistical differences in the percentage and mean optical density for PTEN, CD44between the two groups (p<0.05). Also the average optical density of PTEN, mTOR, NF-κB, CD44and PI3K in nine remission patients were91.16,393.58,642.66,441.78,217.28, meanwhile in eleven relapsed patients, average optical density of PTEN, mTOR, NF-κB, CD44and PI3K were292.51,223.00,775.35,840.06,316.21. There were statistical differences in the percentage and mean optical density for PTEN, CD44between the two groups (p<0.05). Conclusions:①The proportions of CD34+CD123+, CD33+CD123+cells have significant correlation and could be defined as LSC
②The proportion of LSC could be utilized to judge acute leukemia patients station of sustained remission.
③Compound Zhebei Granule can reduce the ratio of CD34+CD123+,CD33+CD123+LSC to improve the efficacy of refractory and relapse acute leukemia when combining chemotherapy, and Compound Zhebei Granule plus chemotherapy has a brilliant application prospect in the efficacy of refractory and relapse acute leukemia.
④High expreesion of CD44could be an important index for diagnosis and prognosis in acute myeloid leukemia. PI3K/Akt/mTOR and NF-κB signal pathway in leukemia cells need further investigation.
1.研究目的
通过观察复方浙贝颗粒联合化疗对难治性急性髓系白血病(acute myeloid leukemia, AML)患者骨髓LSC表面分子标志物的影响及难治性AML患者白血病细胞PI3K/Akt/mTOR信号通路和NF-κB信号通路中相关分子标记物(PI3K、mTOR、PTEN、 NF-κB)与骨髓周围微环境相互作用的细胞表面标记物CD44表达变化,试图明确复方浙贝颗粒逆转多药耐药效应靶点。
2.研究方法
全部病例资料来自北京中医药大学东直门医院血液肿瘤科,北京大学人民医院血液科,廊坊市中医医院血液科于2011年12月至2013年8月观察的难治性AML患者。治疗采用化疗方案有HAE, MA, CAG, AA, EA, FLAG等,复方浙贝颗粒(浙贝母12克,川芎9克,防已9克)由北京康仁堂药业有限公司制成中药配方颗粒,于化疗前3天开始服用复方浙贝颗粒,每次1袋,每日2次,共服用14天,21天为一疗程。以流式细胞术分别检测骨髓有核细胞中LSC表面分子标志物(CD34+CD123+、 CD33+CD123+)细胞表达比例。有30例患者完成治疗前后对照,分别检测了2次LSC表达比例；另外23例患者仅检测了1次LSC表达比例。20例次在北京中医药大学东直门医院血液肿瘤科住院的难治性AML患者行骨髓活检术采集组织标本,以免疫组化技术检测了CD44、PI3K、mTOR、PTEN、NF-κB表达情况。
3.研究结果
①难治AML中CD34+与CD33+CD123+细胞比例分别为11.78%、12.86%,两者相关性分析显示相关系数为0.953,两者具有明显相关性(p<0.001)。②按诊疗标准分类将难治性AML分为两组,其中处于缓解状态时患者的LSC表达比例分别为0.66%,0.92%,较处于复发状态时LSC比例(20.73%,22.47%)明显降低,差异具有统计学意义(p<0.001)。
③30例完成前后治疗对照的难治性AML患者治疗后LSC表面分子标志物细胞表达比例(5.49%,5.94%)较治疗前明显降低(17.05%,17.71%),差异有统计学意义(p<0.05)。其中25例处于复发状态时完成治疗前后对照的患者进一步分析发现,治疗后LSC比例(6.82%,7.39%)也较治疗前LSC比例(21.74%,22.48%)明显降低,差异有统计学意义(p<0.01)。治疗后达到完全缓解有10例患者(有效率40%),且LSC表面分子标志物细胞表达比例分别为1.50%,1.65%,较未缓解患者明显下降(11.65%,12.61%),差异具有统计学意义(p<0.01)。
④20例取骨髓活检患者中9例处于完全缓解的白血病细胞相关分子标记物CD44、PI3K、mTOR.PTEN.NF-κB阳性细胞表达率分别为22.2%、0%、33.3%、33.3%、77.8%,与11例未缓解的63.6%、0%、18.2%、63.6%、90.9%相比,CD44表达差异有统计学意义(p<0.05),阳性表达强度也提示CD44表达在两组间有统计学差异。完全缓解的白血病细胞相关分子标记物CD44.PI3K.mTOR.PTEN.NFκB平均光密度分别为441.78、217.28、393.58、91.16、642.66,与未缓解的840.06、316.21、223.00、292.51、775.35相比,CD44表达差异有统计学意义(p<0.05)。
4.研究结论
①CD34'CD123+与CD33+CD123+细胞具有显著相关,可以用来定位LSC。
②LSC比例可以反映急性白血病患者是否处于持续缓解状态。
③复方浙贝颗粒是通过降低LSC表面分子标记物CD123、CD33表达比例,提高了难治性AML化疗缓解率。
④白血病细胞中CD44高表达可作为难治性AML预后判定的重要参考指标,PI3K/Akt/mTOR信号通路和NF-κB信号通路在白血病细胞中的作用需要进一步研究。
This article contains two parts. From literature review, leukemia stem cell (LSC) which has self renewal capacity and infinite proliferation potential is the root of acute leukemia. LSC is in stationary stage, reluctant to most chemotherapy drugs, and easily causes multidrug resistance in leukemia cells. LSC concentrates in bone marrow niche where chemotherapy drugs can't reach and owns natural resistance characteristics, so LSC can avoid drug's attack to be a risk factor of relapsed acute leukemia. When most acute leukemia patients are in clinical complete remission stage, minimal residual diseases including LSC could repeatedly activate into cell cycles, realize self renewal and infinitely proliferated, then acute leukemia patients will become relapsed. In clinical observation, some refractory acute leukemia patients turn out to serious myelosuppression after chemotherapy, but they will relapse quickly with mass leukemia cells possessing over expression of drug-resistant related proteins in peripheral blood or bone marrow after drugs withdrawl. This indicates that LSC has biological characteristics of high proferation potential and multidrug resistance. Targeting on leukemia stem cell may be one of best therapies to overcome leukemia cells'multidrug resistance. In previous studies, Compound Zhebei Granule plus chemotherapy can improve clinical efficacy of refractory acute leukemia, which curative mechanisms rely on inducing cell apoptosis, down regulating over expression resistant proteins on membrane surface and adjusting abnormal changes of enzymes about multidrug resistance. These studies focus on leukemia cells and lack further researching on its function of leukemia stem cell.
Objective: this thesis is to investigate the efficacy of Compound Zhebei Granule plus chemotherapy on acute myeloid LSC's surface markers, and to detect the expression of PI3K/Akt/mTOR and NF-κB signal pathway biomarkers (PTEN, PI3K, mTOR, NF-κB) and bone marrow peripheral microenviroment' scell surface marker (CD44) related with bone marrow cells in patients with refractory acute myeloid leukemia.
Methods:From December,2011to August,2013, all cases who were candidates for refractory acute myeloid leukemia criteria were included from department of oncology and hematology in Dongzhimen hospital affiliated Beijing University of Traditional Chinese Medicine, department of hematology in Renmin hospital affiliated Beijing University and department of hematology in Langfang hospital of Chinese medicine. The common chemotherapy has HAE, MA, CAG, AA, EA, FLAG, et al. Compound Zhebei Granules are composed of fritillaria12grams,ligust icum9grams and tetrandr ine9grams, and is made into granule by Beijing tcmages pharmaceutical company limited. Compound Zhebei Granules were taken before chemotherapy in three days, once one bag, and twice a day, lasting fourteen days, twenty-one days a treatment cycle. Two milliliters bone marrow were analyzed by flow cytometry to evaluate the quantity of CD34+CD123+、CD33+CD123+leukemia stem cell. Thirty patients had undergone Compound Zhebei Granules plus chemotherapy and were abstracted bone marrow twice, the other twenty three patients were abstracted bone marrow once. Twenty patients in department of oncology and hematology in Dongzhimen hospital affiliated Beijing University of Traditional Chinese Medicine have abstracted bone marrow biopsy, then to do immunohis tochemistry to detect PTEN, PI3K, mTOR, NF-κB and CD44in all the samples. Results:①The proportions of CD34+CD123+, CD33+CD123+cells in refractory AML respectively are11.78%,12.86%, the correlation coefficient between them is0.953, both of them have significant correlation (p<0.001).
②Eighty-three cases of refractory acute leukemia had been tested the proportions of CD34+CD123+, CD33+CD123+cel Is. According to diagnostic criteria and therapeutic standards, the proportions of LSC in refractory AML patients who were under remission stations are0.66%,0.92%, which have a significant decrease when compared with the proportions of leukemia stem cell in refractory AML patients who were under relapsed stations.
③Thirty refractory AML patients had gone through Compound Zhebei Granules plus chemotherapy. Compared with the prior chemotherapy group (17.05%,17.71%), the proportions of LSC cells in post-treatment group (5.49%,5.94%) have a significant decrease (p<0.05). To further investigation, the proportions of leukemia stem cell in twenty-five patients who were under relapsed stations also had a significant decrease when compared with the prior chemotherapy group. Ten patients in twenty-five who were refractory AML patients under relapsed stations had accomplished completely release with the effects of Compound Zhebei Granules plus chemotherapy, and the remission rate is40%. When compared with the unreleased group, the proportions of CD34+CD123+, CD33+CD123+cel Is have a statistical significant reduction (p<0.01)in clinical remission.
④Twenty refractory AML pat ients who have biopsy bone marrow were divided into nine patients who were in remission stations and eleven patients who were unreleased stations. The positive expression rates of PTEN, mTOR, NF- kB, CD44and PI3K in nine remission patients were33.3%,33.3%,77.8%,22.2%and0%, meanwhile in eleven relapsed patients, the positive expression rates were63.6%,18.2%,90.9%,63.6%and0%. There were statistical differences in the percentage and mean optical density for PTEN, CD44between the two groups (p<0.05). Also the average optical density of PTEN, mTOR, NF-κB, CD44and PI3K in nine remission patients were91.16,393.58,642.66,441.78,217.28, meanwhile in eleven relapsed patients, average optical density of PTEN, mTOR, NF-κB, CD44and PI3K were292.51,223.00,775.35,840.06,316.21. There were statistical differences in the percentage and mean optical density for PTEN, CD44between the two groups (p<0.05). Conclusions:①The proportions of CD34+CD123+, CD33+CD123+cells have significant correlation and could be defined as LSC
②The proportion of LSC could be utilized to judge acute leukemia patients station of sustained remission.
③Compound Zhebei Granule can reduce the ratio of CD34+CD123+,CD33+CD123+LSC to improve the efficacy of refractory and relapse acute leukemia when combining chemotherapy, and Compound Zhebei Granule plus chemotherapy has a brilliant application prospect in the efficacy of refractory and relapse acute leukemia.
④High expreesion of CD44could be an important index for diagnosis and prognosis in acute myeloid leukemia. PI3K/Akt/mTOR and NF-κB signal pathway in leukemia cells need further investigation.
引文
[1]Tencate B, Debruyn M, Wei Y, et al. Targeted elimination of leukemia stem cells:a new therapeutic approach in hematooncology[J]. Curr Drug Targets, 2010,11(1):95-110.
[2]李蓉蔚,王诗韵,董慧娟,等.急性髓系白血病干细胞NOD/SCID小鼠白血病模型的建立[J].生物医学工程与临床,2013,17(3)：213-217.
[3]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice[J]. Nature,1994, 367(6464):645-648.
[4]Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3 (7): 730-737.
[5]Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long term proliferative ability in vitro and in vivo have the phenotype CD34+CD71-HLA-DR-[J]. Blood, 1998,92(11):4325-4335.
[6]王颖超,冯磊,殷楚云,等.THP-1细胞系白血病干细胞的检测、分选及鉴定[J].郑州大学学报(医学版),2013,48(2)：210-213.
[7]刘俊,张先平,蔡世忠,等.白血病K562细胞株中CD34+细胞群的分离及其生物学特征[J].中国生物制品学杂志,2013,26(1)：22-26.
[8]王国征,李慧,吴远彬,等.免疫磁珠分选分选白血病KGla细胞中CD34+ CD38-细胞干细胞及其特性研究[J].新乡医学院学报,2013,30(3)：181-184.
[9]Horton SJ, Huntly BJ. Recent advances in acute myeloid leukemia stem cell biology[J].Haematologica,2012,97(7):966-974.
[10]Agrawal-Singh S, Koschmieder S, Gelsing S, et al. Pim2 cooperates with PML-RAR a to induce acute myeloid leukemia in a bone marrow transplantation model [J]. Blood,2010,115(22):4507-4516.
[11]陈运贤,钟雪云.白血病干细胞的靶向治疗[J].中华肿瘤杂志,2006,28(6)：401-403.
[12]Hasse D, Feuring BM, Konemann S, et al. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations[J]. Blood, 1995, 86(8):2906-2912.
[13]Mehrotra B, George TI, Kavanau K, et al. Cytogenetically aberrant cells in the stem cell compartment (CD34+Lin-) in acute myeloid leukemia [J]. Blood, 1995,86(3):1139-1147.
[14]Passegue E, Wagner EF, Weissma IL. JunB deficiency leads to a myeloproliferative disorder arising from hematopoiet ic stem cells[J].Cell, 2004,119(3):431-443.
[15]Shao Shi-hong, Yao Yun-hong. Stem cell, cancer stem cell and cancer[J].Modern Oncology, 2005,13(3):430-432.
[16]Levis M, Kathleenn M. Internal tandem duplications of the FLT3 gene are present in leukemia stem cell [J]. Blood,2005,106(2):673-680.
[17]Cozzio A, Passegue E, Ayton PM, et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors [J]. Genes Dev,2003,17(24):3029-3035.
[18]Huntly BJ, Shigematsu H, Degucchi K, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors[J].Cancer Cell,2004,6(6):587-596.
[19]Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukemia stem cell initiated by MLL-AF9[J]. Nature,2006,442 (7104):818-822.
[20]Stubbs MC, Kim YM, Krivstov AV, et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia:development of a model for rapid therapeutic assessment [J]. Leukemia,2008,22(1):66-77.
[21]Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte macrophage progenitors as candidate leukemic stem cells in blast-crisis CML[J].The New England journal of medicine,2004,351(7):657-667.
[22]Tsuji-Takayama K, Inoue T, Ijiri Y, et al. Demethylating agent, 5-azacytidine, reverses differentiation of embryonic stem cells[J]. Biochem Biophys Res Commun,2004,323(1):86-90.
[23]Von Melchner H, Hoffken K. Human placental conditioned medium reverses apparent commitment to differentiation of human promyelocytic leukemia cells(HL60) [J].Blood,1985,66(6):1469-1472.
[24]Gunsilius E, Duba HC, Petzer AL, et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells[J]. Lancet,2000,355(9216):1688-1691.
[25]林全德,房佰俊,宋永平,等.Bcr/Abl融合基因阳性、Flkl+CD34-慢性粒细胞性白血病干细胞的分离纯化及其生物学特性的研究[J].国际输血及血液学杂志,2006,29(5)：387-391.
[26]Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71 (-)/HLA-DR-[J].Blood,1998,92(11):4325-4335.
[27]Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells[J]. Leukemia,2000,14(10):1777-1784.
[28]Hwang K, Park CJ, Jang S, et al. Flow cytometric quantification and immunopnenotyping of leukemic stem cells in acute myeloid leukemia [J].Ann Hematol,2012,91(10):1541-1546.
[29]Van Rhenen, van Dongen GA, Kelder A, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells[J].Blood,2007,110(7):2659-2666.
[30]Deshpande AJ, Cusan M, Rawat VPS, et al. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia[J]. Cancer Cell,2006,10(5):363-374.
[31]Hosen N, Park CY, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia[J]. Proc Natl Acad Sci USA, 2007, 104(26):11008-11013.
[32]Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells [J]. Cell,2009,138(2):286-299.
[33]Hauswirth AW, Florian S, Printz D, et al. Expression of the target receptor CD33 in CD34 (+)/CD38 (-)/CD123 (+) AML stem eells [J]. Eur J Clin Invest, 2007,37(1):73-82.
[34]Kikushige Y, Shima T, Takayanagi S, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells [J]. Cell Stem Cell, 2010,7(6):708-717.
[35]Terpstra W, Ploemacher RE, Prins A, et al. Fluorouracil selectively spares acute myeloid leukemia cells with long term growth abilities in immunodeficient mice and in culture[J]. Blood,1996,88(6):1944-1950.
[36]Dean M, Fojo T, Bates S. Tumor stem cells and drug resistance [J]. Nat Rev Cancer,2005,5(4):275-284.
[37]Saito Y, Uchida N, Tanaka S. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML[J].Nat Biotechnol,2010, 28(3):275-280.
[38]Reya T, Clevers H. Wnt signal ing in stem cells and caner [J]. Nature,2005, 434(7035):843-850.
[39]Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML[J]. Sience,2010, 327(5973):1650-1653.
[40]Willert K, Jones KA. Wnt signaling: is the party in the nucleus? [J]. Genes Dec,2006,20(11):1394-1404.
[41]Andreeff M, Ruvolo V, Gadgil S, et al. HOX expression patterns identify a common signature for favorable AML[J]. Leukemia,2008,22(11):2041-2047.
[42]Heuser M, Sly LM, Argiropoulos B, et al. Modeling the functional heterogenetity of leukemia stem cells:role of STAT5 in leukemia stem cell self-renewal [J]. Blood,2009,114(19):3983-3993.
[43]Oguro H, Yuan J, Ichikawa H, et al. Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmil [J]. Cell Stem Cell,2010,6(3):279-286.
[44]Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notchl signaling[J]. Nat Med,2000,6(11):1278-1281.
[45]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of micro environmental interactions in leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
[46]Konopleva M, Zhao S, Hu W, et al. The ant i-apoptotic genes Bcl-X(L) and Bc1-2 are overexpressed and contribute to chemoresistance of nonproliferating leukemic CD34+cell[J].Br J Haematol,2002,118(2): 521-534.
[47]Breccia M, Alimena G. NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia[J].Expert Opin Ther Targets,2010,14(11):1157-1176.
[48]Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells [J]. Blood,2001,98(8):2301-2307.
[49]Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia[J]. Leukemia,2006,20(6):911-928.
[50]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells[J]. Nature,2006, 441(7092):475-482.
[51]郑瑞,陈葆国,干灵红,等.急性髓系白血病干细胞免疫表型和信号通路蛋白活化检测及意义[J].医学研究杂志,2011,40(11)：89-93.
[52]Flynn CM, Kaufman DS. Donor cell leukemia:insight into cancer stem cells and the stem cell niche[J]. Blood,2007,109(7):2688-2692.
[53]Scadden DT. The stem cell niche in health and leukemic disease [J].Best Pract Res Clin Haematol,2007,20(1):19-27.
[546]Carlesso N, Cardoso AA. Stem cell regulatory niches and their role in normal and malignant hema topoies is [J]. Curr Opin llematol,2010, 17(4): 281-286.
[55]Wei J, Wunderlich M, Fox C, et al. Microenviroment determines lineage fate in a human model of MLL-AF9 leukemia[J]. Cancer Cell,2008,13(6): 483-495.
[56]Williams DA, Cancelas JA. Leukemia: niche retreats for stem cells[J]. Nature,2006,444(7121):827-828.
[57]支蕾,王琳,田征,等.N-cadherin在维持白血病干细胞特征中的作用[J].中国实验血液学杂志,2010,18(1)：7-10.
[58]Misaghian N, Ligreti G, Steelman LS, et al. Targeting the leukemic stem cell:the Holy Grail of leukemia therapy[J]. Leukemia, 2009,23(1):25-42.
[59]于沛,邱少伟,饶青,等.c-MPL在急性髓系白血病患者白血病干细胞中的表达[J].中国实验血液学杂志,2012,20(5)：1052-1055.
[60]Vaiselbuh SR, Edelman M, Lipton JM, et al. Ectopic human mesenchymal stem cell-coated scaffolds in NOD/SCID mice: An invivo model of the leukemia niche [J]. Tissue Eng Part C Methods,2010, 16(6):1523-1531.
[61]Tavor S, Petit L, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice[J]. Cancer Res,2004,64(8):2817-2824.
[62]Matsunaqa T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia[J]. Nat Med, 2003,9(9):1158-1165.
[63]Gerber JM, Smith BD, Nqwanq B, et al. A clinically relevant population of leukemic CD34+CD38-cells in acute myeloid leukemia[J]. Blood,2012, 119(15):3571-3577.
[64]Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial[J]. J Clin Oncol,2011,29(4): 369-377.
[65]Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells[J]. Cell Stem Cell,2009,5(1):31-42.
[66]Feuring-Buske M, Frankel AE, Alexander RL, et al. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to Primitive acute myeloid leukemia progenitors but spares normal progenitors[J]. Cancer Res,2002, 62(6):1730-1736.
[67]Frankel A, Liu JS, Rizzieri D, et al. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia [J]. Leuk Lymphoma,2008,49(3):543-553.
[68]Kim HP, Frankel AE, Hogge DE. A diphtheria toxin interleukin-3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from BCR/ABL positive acute leukemia[J].Leuk Res,2010,34(8): 1035-1042.
[69]Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis[J].Cell, 2009,138(2):271-285.
[70]Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells[J].Cell,2009,138(2):286-299.
[71]王颖超,冯磊,殷楚云,等.抗CD47抗体联合阿糖胞苷靶向治疗NOD/SCID小鼠单核细胞白血病的研究[J].中国当代儿科杂志,2013,15(7)：577-582.
[72]宋盈盈,苏荣英,艾丽梅.树突状细胞-细胞因子诱导杀伤细胞体外抗白血病K562细胞的效应[J].中国组织工程研究与临床康复,2010,14(49)：9208-9211.
[73]张阳,张连生,曾鹏云,等DC-CIK对急性髓细胞白血病干细胞的杀伤作用[J].中国肿瘤生物治疗杂志,2011,18(4)：404-408.
[74]庞华,孙雯雯,梁芳芳,等LSC-DC-CIK对慢性粒细胞白血病细胞干细胞杀伤作用的体外试验研究[J].中国慢性疾病预防与控制,2012,21(1)：26-29.
[75]梁芳芳,庞华,司玉玲,等.干细胞来源DC与CIK共培养抗K562/A02干细胞的体外研究[J].天津医药,2013,41(4)：289-292.
[76]Kirchner D, Duyster J, Ottmann O, et al. Mechanisms of Bcr-Abl-mediated NF-kappa B/Rel activation [J]. Exp Hematol,2003,31(6):504-511.
[77]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental nteractions n leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
[78]Burger JA, Peled A. CXCR4 antagonists:targeting the microenvironment in leukemia and other cancers [J]. Leukemia,2009,23(1):43-52.
[79]Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenviroment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML[J]. Blood,2009,113(24):6215-6224.
[80]杨文华,吕俊秀,杨向东,等.蝎毒多肽提取物对白血病小鼠E-钙黏蛋白、CD49d和CXCR4表达的影响[J].时珍国医国药,2010,21(2)：259-263.
[81]Orian-Rousseau V. CD44, a therapeutic target for metastasizing tumours [J]. Eur J Cancer,2010,46(7):1271-1277.
[82]Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemia stem cell [J]. Nat Med,2006,12(10):1167-1174.
[83]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental nteractions n eukemia:Mechanisms and approaches [J]. Drug Resist Updat,2009,12(4-5):103-113.
[84]章龙珍,丁听,李向阳,等.抗CD44单克隆抗体IM7在体外诱导慢性髓系白血 病干/祖细胞的凋亡[J].中国实验血液学杂志,2010,18(3)：601-605.
[85]Cater BZ, Mak DH, Cortes J, et al. The Elusive chronic myeloid leukemia stem cell:Does it matter and how do we eliminate it? [J]. Sem Hematol,2010, 147(4):362-370.
[86]Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells [J]. Proc Natl Acad Sci USA, 2002,99(25):16220-16225.
[87]Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells[J]. Blood, 2005,105(11):4163-4169.
[88]易娟,陈静,孙静,等.小白菊内酯对白血病K562细胞及其干细胞的作用[J].中国中药杂志,2010,35(2)：219-222.
[89]Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells [J]. Blood, 2007,110(13):4427-4435.
[90]Neelakantan S, Nasim S, Guzman et al. Aminoparthenolides as novel anti-leukemic agents:Discovery of the NF-kappa B inhibitor, DMAPT (LC-1) [J].Bioorg Med Chem Lett,2009,19 (15):4346-4354.
[91]Jin Y, Lu Z, Ding K, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells:inactivation of the NF-kappaB pathway and generation of reactive oxygen species [J].Cancer Res,2010,70(6): 2516-2527.
[92]查洁,张妍琰,王诗韵,等.Disulfiram联合Cu对淋巴瘤Raji细胞增殖与凋亡影响及其机制的探讨[J].中华肿瘤防治杂志,2012,19(2)：81-83.
[93]Xu B, Shi PC, Fombon IS, et al. Disulfiram/copper complex activated JNK/c-jun pathway and sensitised cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J].Blood Cells Mol Dis,2011,47(4):264-269.
[94]王诗韵,查洁,董慧娟,等.DC/Cu对急性髓系白血病干细胞增殖与凋亡影响及其机制的探讨[J].中华肿瘤防治杂志,2013,20(6)：411-415.
[95]Aguilar-Morante D, Morales-Garcia JA, Sanz-SanCristobal M, et al. Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8[J].PLoS One,2010,5(11):13879.
[96]Guzman L, Li X, Corbett CA, et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl,1,2,4-thiadiazoline,3,5 dione (TDZD-8) [J]. Blood,2007,110(13): 4436-4444.
[97]Birkenkamp KU, Geuqien M, Scjepers H, et al. Constitutive NF-kappa B DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway [J]. Leukemia,2004,18(1):103-112.
[98]高莹莹,胡亮杉,韩慧娟,等.NVP-BEZ235抑制CD34+CD38-急性髓系白血病干细胞的增殖和集落形成[J].中国实验血液学杂志,2013,21(2)：334-338.
[99]Cheung AM, Mak TW. PTEN in the haematopoietic system and its therapeutic indications[J]. Trends Mol Med,2006,12(11):503-505.
[1]平宝红,孟凡义.肿瘤多药耐药逆转研究现状[J].白血病,2000,9(5)：314-316.
[2]董颖,陈宝安,林果为.拓扑异构酶Ⅱ与白血病多药耐药[J].国外医学：输血及血液学分册,2000,23(3)：181-183.
[3]Konoplcva M, Tari AM, Estrov E, et al. Liposomal Bcl-2 antisense ol igonucleotides enhance proliferatio, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins[J]. Blood, 2000,95(12):3929-3938.
[4]Dean M, Fojo T, Bates S. Tumor stem cells and drug resistance [J]. Nat Rev Cancer,2005,5(4):275-284.
[5]王颖超,冯磊,殷楚云,等.THP-1细胞系白血病干细胞的检测、分选及鉴定[J].郑州大学学报(医学版),2013,48(2)：210-213.
[6]刘俊,张先平,蔡世忠,等.白血病K562细胞株中CD34+细胞群的分离及其生物学特征[J].中国生物制品学杂志,2013,26(1)：22-26.
[7]Ho MM, Hogge DE, Ling V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia[J].Exp Hemato,2008,36(4):433-442.
[8]Marques DS, Sandrini JZ, Boyle RT, et al. Relationships between multidrug resistance (MDR) and stem cell markers inhuman chronic myeloid leukemia cell lines [J].Leuk Res,2010,34(6):757-762.
[9]Merchant AA, Matusi W. Targeting hedgehog a cancer stem cell pathway [J].Clin Cancer Res,2010, 16(12):3130-3140.
[10]Qadir M, O' Loughlin KL, Fricke SM, et al. Cyclosporin A is a broad-spectrum multidrug resistance modulator[J]. Clin Cancer Res,2005, 11(6):2320-2326.
[11]Jurecekova J, Hatok J, Stefanikova A, et al. Targeting of Bcl-2 family proteins for treatment of acute leukaemia [J]. Gen Physiol Biophys,2011,30 Spec No:S3-S12.
[12]Del PG, Bruno A, Del PM, et al. Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia[J]. Curr Cancer Drug Targets,2008,8(3):207-222.
[13]van Stijn A, van der Pol MA, Kok A, et al. Differences between the CD34+ and CD34- blast compartments in apoptosis resistance in acute myeloid leukemia [J]. Haematologica,2003,88(5):497-508.
[14]Costello RT, Mallet F, Gauqler B, et al. Human acute myeloid leukemia CD34+/CD38-progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities[J]. Cancer Res,2000,60(16):4403-4411.
[15]Queiroz KC, Ruela-De-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells[J]. Oncogene,2010, 29(48):6314-6322.
[16]Kobune M, Takimoto R, Murase K, et al. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+leukemic cells [J]. Cancer Sci,2009, 100(5):948-955.
[17]Neering SJ, Bushnell T, Sozer S, et al. Leukemia stem cells in a genetically defined murine model of blast crisis CML [J]. Blood,2007,110(7): 2578-2585.
[18]Eyler CE, Rich JN. Survival of the fittest:cancer stem cells in therapeutic resistance and angiogenesis[J].Clin Oncol,2008,26(17): 2839-2845.
[19]Guo BW, Xiao QC, Qi RG, et al. Arsenic Trioxide overcomes cell adhesion-mediated drug res i stance through down-regulating the expression of beta(1)-integrin in K562 chronic myelogenous leukemia cell line[J].Leuk Lymphoma, 2010,51(6):1090-1097.
[20]何侃,于沛,邢海燕,等N-cadherin阳性白血病KG1a细胞系在G0期抵抗VP16杀伤的作用[J].中国实验血液学杂志,2011,19(5)：1102-1106.
[21]胡婕,张茵,马保根,等.雷公藤红素逆转K 562/A02细胞多药耐药的实验研究[J].实用癌症杂志,2011,26(3)：226-229.
[22]蔡讯,陈芳源,韩洁英,等.槲皮素逆转白血病细胞株HL-60/ADM多药耐药的研究[J].中华肿瘤杂志,2005,27(6)：326-329.
[23]王为光,于广晴,张国艳,等.槲皮素体外逆转K562/ADM耐药的研究[J].黑龙江医药科学,2011,34(2)：28-29.
[24]陈玉英,李静,胡建达,等.大黄素对HL-60/ADR耐药细胞多药耐药逆转作用的研究[J].中国实验血液学杂志,2013,21(6)：1413-1422.
[25]陈宝安,李静,程坚,等.汉防已甲素联合柔红霉素对K562/A02细胞株P21蛋白和P糖蛋白表达的影响[J].中国实验血液学杂志,2009,17(5)：1179-1182.
[26]曹渊,方悦,秦蓉,等.汉防已甲素预防裸鼠白血病多药耐药性形成的研究[J].健康研究,2013,33(5)：335-338.
[27]马海英,赵瑾瑶,金伟,等.川芎嗪对转基因多药耐药细胞K562/MDR耐药性的逆转作用[J].吉林大学学报(医学版),2009,35(4)：599-602.
[28]李菲,张荣艳,邢娟娟.三氧化二砷逆转白血病细胞多药耐药的作用及机制[J].山东医药,2008,48(25)：30-31.
[29]王婷,双跃荣,庄小捷.川芎嗪联合三氧化二砷逆转K562/ADM细胞多药耐药的实验研究[J].实用癌症杂志,2009,34(2)：121-124.
[30]张怡敏,董邦权,海文利,等.姜黄素对耐药细胞株K562/ADM的耐药逆转作用研究[J].细胞与分子免疫学杂志,2009,25(10)：958-962.
[31]盖晓东,历春,李倩,等.柴胡皂苷在体外对人白血病细胞株K562/ADM多药耐药性的逆转作用[J].中国病理生理杂志,2012,28(1)：76-80.
[32]赵早云.毛冬青甲素对白血病细胞K562/A02多药耐药蛋白P-170的影响[J].光明中医,2010,25(7)：1165-1166.
[33]许静,李瑞明, 肖希斌,等.木犀草素抑制白血病耐药株K562/A02的GST-π表达[J].今日药学,2012,22(1)：7-9.
[34]杨莉洁,赵挺,白庆咸,等.黄芩苷对白血病细胞耐药株逆转耐药效果及机制 研究[J].陕西医学杂志,2012,41(7)：775-778.
[35]黄望香,曾雪花,李翠霞,等.双氢青蒿素对白血病多药耐药K562/ADM细胞的逆转作用[J].医学理论与实践,2012,25(15)：1810-1812.
[36]田亮,刘娟,陈宝安,等.藤黄酸对白血病K562/A02细胞的耐药逆转作用[J].中国实验血液学杂志,2012,20(2)：252-257.
[37]秦小清,梁宇光,高洪志,等.五味子甲素对K562/ADR、HL60/ADR、MCF-7/ADR多药耐药逆转机制的研究[J].中国药理学通报,2011,27(3)：329-334.
[38]石倩倩,丁亚辉,祁瑞哲,等.小白菊内酯诱导耐药白血病细胞K562/ADR凋亡的研究[J].中国药理学通报,2012,28(12)：1736-1740.
[39]方凡夫,张亚妮,顾伟.蟾毒灵抑制人白血病多药耐药K562/VCR细胞株增殖的实验研究[J].中药新药与临床药理,2010,21(3)：213-215.
[40]胡美薇,张越峰,姚国丽.鸦胆子油乳抑制人白血病多药耐药K562/VCR细胞株增殖的实验研究[J].浙江实用医学,2012,17(5)：315-317.
[41]彭向前,杨培民,吴慧,等.半夏水提取液逆转多药耐药细胞系K562/A02耐药性的研究[J].齐鲁药事,2012,31(7)：385-387.
[42]李洁,刘盼盼.半枝莲逆转白血病细胞株K562/A02耐药性的实验研究[J].中医药导报,2012,18(5)：88-89.
[43]熊新,周远大.蟾蜍注射液逆转HL60/阿霉素细胞多药耐药的机制[J].南方医科大学学报,2012,32(3)：337-380.
[44]李秀军,严鲁萍,姚宇红.扶正祛邪中药复方含药血清抗白血病细胞HL60及HL60/VCR细胞的体外实验研究[J].广东医学,2012,33(7)：896-897.
[45]马武开,李玉莹,姚血明,等.白血病HL60/ADR细胞Mdrl、NF-κB的表达及解毒化瘀药的干预作用[J].西安交通大学学报,2011,32(5)：592-595.
[46]马武开,姚血明,唐芳,等.解毒化瘀药对白血病K562/A02耐药细胞mdrl耐药基因、核因子κB信号影响的研究[J].重庆医科大学学报,2011,36(8)：897-899.
[47]马武开,姚血明,王莹,等.解毒化瘀药含药血清对白血病HL60/ADR耐药细胞NF-κB信号靶向干预研究[J].中国实验方剂学杂志,2011,17(18)：154-157.
[48]廖斌,葛仁英,徐成波,等.中药复方君子汤对白血病细胞株K562/VCR耐药性的逆转作用[J].福建中医药大学学报,2011,21(4)：9-12.
[49]林潇,盛国良,孙付军,等.黄连解毒汤所含黄芩苷、京尼平苷对K562/ADM细胞多药耐药相关基因表达的影响[J].中药药理与临床,2012,28(6)：20-24.
[50]史哲新,杨向东,高宏,等.益气养阴法对微小残留白血病多药耐药相关因子的影响[J].天津中医药,2009,26(6)：453-454.
[51]李冬云,陈信义,侯丽,等.从痰瘀论治难治性白血病[J].中国中医基础理论杂志,2009,15(5)：365-367.
[52]李冬云,陈信义,许亚梅.难治性急性白血病研究现状与进展[J].现代生物医学进展,2007,7(8)：1239-1246.
[53]李冬云,陈信义,姜靖雯.复方浙贝颗粒研究现状与应用前景分析[J].中国药 物与临床,2009,9(2)：85-87.
[54]张寅,李冬云,田劭丹,等.复方浙贝颗粒配方伍用化疗治疗难治性急性白血病临床研究[J].河北中医药学报,2006,21(4)：9-11.
[55]李冬云,田劭丹,叶霈智,等.复方浙贝颗粒辅助化疗提高难治性急性白血病临床疗效研究[J].北京中医,2007,26(2)：70-72.
[56]李冬云,郑智,侯丽,等.复方浙贝药物血清抑制L1210/CDDP细胞增殖与诱导凋亡研究[J].现代生物医学进展,2009,9(13)：2413-2416.
[57]郑智,李冬云,陈信义.复方浙贝药物血清影响K562/A02细胞积聚外排功能和细胞凋亡研究[J].中国中西医结合杂志,2010,30(2)：170-173.
[58]郑智,李冬云,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤抑瘤率影响研究[J].当代医学,2010,16(1)：5-6.
[59]郑智,陈菊,李冬云,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤mdrl基因表达的影响[J].中西医结合学报,2009,7(8)：758-762.
[60]陈信义,郑智,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞凋亡及相关蛋白表达的影响[J].中国实验血液学杂志,2009,17(6)：1439-1442.
[61]郑智,侯丽,许亚梅,等.复方浙贝颗粒联合阿霉素影响K562/A02移植瘤细胞耐药相关酶表达研究[J].医学研究杂志,2009,38(12)：29-31.
[62]李冬云,郑智,侯丽,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞膜转运蛋白表达的影响.中国实验血液学杂志,2010,18(1)：1-4.
[1]Felipe Rico J, Has sane DC, Guzman ML. Acute myelogenous leukemia stem cells: From Bench to Bedside[J].Cancer Lett,2013,338(1):4-9.
[2]李冬云,田劭丹,叶霈智,等.复方浙贝颗粒辅助化疗提高难治性急性白血病临床疗效研究[J].北京中医,2007,26(2)：70-72.
[3]郑智,李冬云,陈信义.复方浙贝药物血清影响K562/A02细胞积聚外排功能和细胞凋亡研究[J].中国中西医结合杂志,2010,30(2)：170-173.
[4]陈信义,郑智,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞凋亡及相关蛋白表达的影响[J].中国实验血液学杂志,2009,17(6)：1439-1442.
[5]郑智,侯丽,许亚梅,等.复方浙贝颗粒联合阿霉素影响K562/A02移植瘤细胞耐药相关酶表达研究[J].医学研究杂志,2009,38(12)：29-31.
[6]张之南,沈悌.血液病诊断及疗效标准[M].第3版.北京：科学技术出版社,2007：103-116.
[7]陈运贤,丁倩.白血病治疗新靶点—白血病干细胞[J].新医学,2008,39(9)：613-614.
[8]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice[J]. Nature,1994, 367(6764):645-648.
[9]Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML) [J]. Blood, 2003,101(8):3142-3149.
[10]Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells [J]. Blood, 2005,106(2): 673-680.
[11]Ho MM, Hogge DE, Ling V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia [J].Exp Hemato,2008,36(4):433-442.
[12]Jurecekova J, Hatok J, Stefanikova A, et al. Targeting of Bcl-2 family proteins for treatment of acute leukaemia [J].Gen Physiol Biophys,2011,30 Spec No: S3-S12.
[13]Costello RT, Mallet F, Gauqler B, et al. Human acute myeloid leukemia CD34+/CD38-progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities[J]. Cancer Res,2000, 60(16):4403-4411.
[14]Jin L, LEE EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells[J].Cell Stem Cell,2009,5(1):31-42.
[15]Feuring-Buske M, Frankel AE, Alexander RL, et al. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to Primitive acute myeloid leukemia progenitors but spares normal progenitors[J]. Cancer Res,2002,62(6): 1730-1736.
[16]Frankel A, LiuJ S, Rizzieri D, etal. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia[J]. Leuk Lymphoma,2008,49(3):543-553.
[17]张砚君,李双静,姜琳琳,等IL-3-LDM融合蛋白对CD123+白血病细胞的靶向杀伤作用[J].中国肿瘤生物治疗杂志,2013,20(4)：391-397.
[18]Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial[J]. J Clin Oncol,2011,29(4): 369-377.
[19]Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells[J]. Blood,2001,98(8):2301-2307.
[20]Martelli AM, Nyakern M, TabelliniG, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia[J]. Leukemia,2006,20(6):911-928.
[21]陆荣. 白血病发病与骨髓微环境的关系[J].医学综述,2011,17(18)：2762-2765.
[22]Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells[J]. Blood,2005,105(11):4163-4169.
[23]Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells[J]. Blood,2007,110(13):4427-4435.
[24]Neelakantan S, Nasim S, Guzman et al. Aminoparthenolides as novel anti-leukemic agents:Discovery of the NF-kappa B inhibitor, DMAPT (LC-1) [J]. Bioorg Med Chem Lett,2009,19 (15):4346-4354.
[25]Birkenkamp KU, Geuqien M, Scjepers H, et al. Constitutive NF-kappa B DNA-binding activity n AML s frequently ediated by a Ras/PI3-K/PKB-dependent pathway [J].Leukemia,2004,18(1):103-112.
[26]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells[J]. Nature,2006, 441(7092):475-482.
[27]Cheung AM, Mak TW. PTEN in the haematopoietic system and its therapeutic indications [J]. Trends Mol Med,2006,12(11):503-505.
[28]Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemia stem cells [J]. Nat Med, 2006,12(10):1167-1174.
[29]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental interactions in leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
[2]李蓉蔚,王诗韵,董慧娟,等.急性髓系白血病干细胞NOD/SCID小鼠白血病模型的建立[J].生物医学工程与临床,2013,17(3)：213-217.
[3]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice[J]. Nature,1994, 367(6464):645-648.
[4]Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3 (7): 730-737.
[5]Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long term proliferative ability in vitro and in vivo have the phenotype CD34+CD71-HLA-DR-[J]. Blood, 1998,92(11):4325-4335.
[6]王颖超,冯磊,殷楚云,等.THP-1细胞系白血病干细胞的检测、分选及鉴定[J].郑州大学学报(医学版),2013,48(2)：210-213.
[7]刘俊,张先平,蔡世忠,等.白血病K562细胞株中CD34+细胞群的分离及其生物学特征[J].中国生物制品学杂志,2013,26(1)：22-26.
[8]王国征,李慧,吴远彬,等.免疫磁珠分选分选白血病KGla细胞中CD34+ CD38-细胞干细胞及其特性研究[J].新乡医学院学报,2013,30(3)：181-184.
[9]Horton SJ, Huntly BJ. Recent advances in acute myeloid leukemia stem cell biology[J].Haematologica,2012,97(7):966-974.
[10]Agrawal-Singh S, Koschmieder S, Gelsing S, et al. Pim2 cooperates with PML-RAR a to induce acute myeloid leukemia in a bone marrow transplantation model [J]. Blood,2010,115(22):4507-4516.
[11]陈运贤,钟雪云.白血病干细胞的靶向治疗[J].中华肿瘤杂志,2006,28(6)：401-403.
[12]Hasse D, Feuring BM, Konemann S, et al. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations[J]. Blood, 1995, 86(8):2906-2912.
[13]Mehrotra B, George TI, Kavanau K, et al. Cytogenetically aberrant cells in the stem cell compartment (CD34+Lin-) in acute myeloid leukemia [J]. Blood, 1995,86(3):1139-1147.
[14]Passegue E, Wagner EF, Weissma IL. JunB deficiency leads to a myeloproliferative disorder arising from hematopoiet ic stem cells[J].Cell, 2004,119(3):431-443.
[15]Shao Shi-hong, Yao Yun-hong. Stem cell, cancer stem cell and cancer[J].Modern Oncology, 2005,13(3):430-432.
[16]Levis M, Kathleenn M. Internal tandem duplications of the FLT3 gene are present in leukemia stem cell [J]. Blood,2005,106(2):673-680.
[17]Cozzio A, Passegue E, Ayton PM, et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors [J]. Genes Dev,2003,17(24):3029-3035.
[18]Huntly BJ, Shigematsu H, Degucchi K, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors[J].Cancer Cell,2004,6(6):587-596.
[19]Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukemia stem cell initiated by MLL-AF9[J]. Nature,2006,442 (7104):818-822.
[20]Stubbs MC, Kim YM, Krivstov AV, et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia:development of a model for rapid therapeutic assessment [J]. Leukemia,2008,22(1):66-77.
[21]Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte macrophage progenitors as candidate leukemic stem cells in blast-crisis CML[J].The New England journal of medicine,2004,351(7):657-667.
[22]Tsuji-Takayama K, Inoue T, Ijiri Y, et al. Demethylating agent, 5-azacytidine, reverses differentiation of embryonic stem cells[J]. Biochem Biophys Res Commun,2004,323(1):86-90.
[23]Von Melchner H, Hoffken K. Human placental conditioned medium reverses apparent commitment to differentiation of human promyelocytic leukemia cells(HL60) [J].Blood,1985,66(6):1469-1472.
[24]Gunsilius E, Duba HC, Petzer AL, et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells[J]. Lancet,2000,355(9216):1688-1691.
[25]林全德,房佰俊,宋永平,等.Bcr/Abl融合基因阳性、Flkl+CD34-慢性粒细胞性白血病干细胞的分离纯化及其生物学特性的研究[J].国际输血及血液学杂志,2006,29(5)：387-391.
[26]Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71 (-)/HLA-DR-[J].Blood,1998,92(11):4325-4335.
[27]Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells[J]. Leukemia,2000,14(10):1777-1784.
[28]Hwang K, Park CJ, Jang S, et al. Flow cytometric quantification and immunopnenotyping of leukemic stem cells in acute myeloid leukemia [J].Ann Hematol,2012,91(10):1541-1546.
[29]Van Rhenen, van Dongen GA, Kelder A, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells[J].Blood,2007,110(7):2659-2666.
[30]Deshpande AJ, Cusan M, Rawat VPS, et al. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia[J]. Cancer Cell,2006,10(5):363-374.
[31]Hosen N, Park CY, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia[J]. Proc Natl Acad Sci USA, 2007, 104(26):11008-11013.
[32]Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells [J]. Cell,2009,138(2):286-299.
[33]Hauswirth AW, Florian S, Printz D, et al. Expression of the target receptor CD33 in CD34 (+)/CD38 (-)/CD123 (+) AML stem eells [J]. Eur J Clin Invest, 2007,37(1):73-82.
[34]Kikushige Y, Shima T, Takayanagi S, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells [J]. Cell Stem Cell, 2010,7(6):708-717.
[35]Terpstra W, Ploemacher RE, Prins A, et al. Fluorouracil selectively spares acute myeloid leukemia cells with long term growth abilities in immunodeficient mice and in culture[J]. Blood,1996,88(6):1944-1950.
[36]Dean M, Fojo T, Bates S. Tumor stem cells and drug resistance [J]. Nat Rev Cancer,2005,5(4):275-284.
[37]Saito Y, Uchida N, Tanaka S. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML[J].Nat Biotechnol,2010, 28(3):275-280.
[38]Reya T, Clevers H. Wnt signal ing in stem cells and caner [J]. Nature,2005, 434(7035):843-850.
[39]Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML[J]. Sience,2010, 327(5973):1650-1653.
[40]Willert K, Jones KA. Wnt signaling: is the party in the nucleus? [J]. Genes Dec,2006,20(11):1394-1404.
[41]Andreeff M, Ruvolo V, Gadgil S, et al. HOX expression patterns identify a common signature for favorable AML[J]. Leukemia,2008,22(11):2041-2047.
[42]Heuser M, Sly LM, Argiropoulos B, et al. Modeling the functional heterogenetity of leukemia stem cells:role of STAT5 in leukemia stem cell self-renewal [J]. Blood,2009,114(19):3983-3993.
[43]Oguro H, Yuan J, Ichikawa H, et al. Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmil [J]. Cell Stem Cell,2010,6(3):279-286.
[44]Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notchl signaling[J]. Nat Med,2000,6(11):1278-1281.
[45]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of micro environmental interactions in leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
[46]Konopleva M, Zhao S, Hu W, et al. The ant i-apoptotic genes Bcl-X(L) and Bc1-2 are overexpressed and contribute to chemoresistance of nonproliferating leukemic CD34+cell[J].Br J Haematol,2002,118(2): 521-534.
[47]Breccia M, Alimena G. NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia[J].Expert Opin Ther Targets,2010,14(11):1157-1176.
[48]Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells [J]. Blood,2001,98(8):2301-2307.
[49]Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia[J]. Leukemia,2006,20(6):911-928.
[50]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells[J]. Nature,2006, 441(7092):475-482.
[51]郑瑞,陈葆国,干灵红,等.急性髓系白血病干细胞免疫表型和信号通路蛋白活化检测及意义[J].医学研究杂志,2011,40(11)：89-93.
[52]Flynn CM, Kaufman DS. Donor cell leukemia:insight into cancer stem cells and the stem cell niche[J]. Blood,2007,109(7):2688-2692.
[53]Scadden DT. The stem cell niche in health and leukemic disease [J].Best Pract Res Clin Haematol,2007,20(1):19-27.
[546]Carlesso N, Cardoso AA. Stem cell regulatory niches and their role in normal and malignant hema topoies is [J]. Curr Opin llematol,2010, 17(4): 281-286.
[55]Wei J, Wunderlich M, Fox C, et al. Microenviroment determines lineage fate in a human model of MLL-AF9 leukemia[J]. Cancer Cell,2008,13(6): 483-495.
[56]Williams DA, Cancelas JA. Leukemia: niche retreats for stem cells[J]. Nature,2006,444(7121):827-828.
[57]支蕾,王琳,田征,等.N-cadherin在维持白血病干细胞特征中的作用[J].中国实验血液学杂志,2010,18(1)：7-10.
[58]Misaghian N, Ligreti G, Steelman LS, et al. Targeting the leukemic stem cell:the Holy Grail of leukemia therapy[J]. Leukemia, 2009,23(1):25-42.
[59]于沛,邱少伟,饶青,等.c-MPL在急性髓系白血病患者白血病干细胞中的表达[J].中国实验血液学杂志,2012,20(5)：1052-1055.
[60]Vaiselbuh SR, Edelman M, Lipton JM, et al. Ectopic human mesenchymal stem cell-coated scaffolds in NOD/SCID mice: An invivo model of the leukemia niche [J]. Tissue Eng Part C Methods,2010, 16(6):1523-1531.
[61]Tavor S, Petit L, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice[J]. Cancer Res,2004,64(8):2817-2824.
[62]Matsunaqa T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia[J]. Nat Med, 2003,9(9):1158-1165.
[63]Gerber JM, Smith BD, Nqwanq B, et al. A clinically relevant population of leukemic CD34+CD38-cells in acute myeloid leukemia[J]. Blood,2012, 119(15):3571-3577.
[64]Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial[J]. J Clin Oncol,2011,29(4): 369-377.
[65]Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells[J]. Cell Stem Cell,2009,5(1):31-42.
[66]Feuring-Buske M, Frankel AE, Alexander RL, et al. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to Primitive acute myeloid leukemia progenitors but spares normal progenitors[J]. Cancer Res,2002, 62(6):1730-1736.
[67]Frankel A, Liu JS, Rizzieri D, et al. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia [J]. Leuk Lymphoma,2008,49(3):543-553.
[68]Kim HP, Frankel AE, Hogge DE. A diphtheria toxin interleukin-3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from BCR/ABL positive acute leukemia[J].Leuk Res,2010,34(8): 1035-1042.
[69]Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis[J].Cell, 2009,138(2):271-285.
[70]Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells[J].Cell,2009,138(2):286-299.
[71]王颖超,冯磊,殷楚云,等.抗CD47抗体联合阿糖胞苷靶向治疗NOD/SCID小鼠单核细胞白血病的研究[J].中国当代儿科杂志,2013,15(7)：577-582.
[72]宋盈盈,苏荣英,艾丽梅.树突状细胞-细胞因子诱导杀伤细胞体外抗白血病K562细胞的效应[J].中国组织工程研究与临床康复,2010,14(49)：9208-9211.
[73]张阳,张连生,曾鹏云,等DC-CIK对急性髓细胞白血病干细胞的杀伤作用[J].中国肿瘤生物治疗杂志,2011,18(4)：404-408.
[74]庞华,孙雯雯,梁芳芳,等LSC-DC-CIK对慢性粒细胞白血病细胞干细胞杀伤作用的体外试验研究[J].中国慢性疾病预防与控制,2012,21(1)：26-29.
[75]梁芳芳,庞华,司玉玲,等.干细胞来源DC与CIK共培养抗K562/A02干细胞的体外研究[J].天津医药,2013,41(4)：289-292.
[76]Kirchner D, Duyster J, Ottmann O, et al. Mechanisms of Bcr-Abl-mediated NF-kappa B/Rel activation [J]. Exp Hematol,2003,31(6):504-511.
[77]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental nteractions n leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
[78]Burger JA, Peled A. CXCR4 antagonists:targeting the microenvironment in leukemia and other cancers [J]. Leukemia,2009,23(1):43-52.
[79]Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenviroment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML[J]. Blood,2009,113(24):6215-6224.
[80]杨文华,吕俊秀,杨向东,等.蝎毒多肽提取物对白血病小鼠E-钙黏蛋白、CD49d和CXCR4表达的影响[J].时珍国医国药,2010,21(2)：259-263.
[81]Orian-Rousseau V. CD44, a therapeutic target for metastasizing tumours [J]. Eur J Cancer,2010,46(7):1271-1277.
[82]Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemia stem cell [J]. Nat Med,2006,12(10):1167-1174.
[83]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental nteractions n eukemia:Mechanisms and approaches [J]. Drug Resist Updat,2009,12(4-5):103-113.
[84]章龙珍,丁听,李向阳,等.抗CD44单克隆抗体IM7在体外诱导慢性髓系白血 病干/祖细胞的凋亡[J].中国实验血液学杂志,2010,18(3)：601-605.
[85]Cater BZ, Mak DH, Cortes J, et al. The Elusive chronic myeloid leukemia stem cell:Does it matter and how do we eliminate it? [J]. Sem Hematol,2010, 147(4):362-370.
[86]Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells [J]. Proc Natl Acad Sci USA, 2002,99(25):16220-16225.
[87]Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells[J]. Blood, 2005,105(11):4163-4169.
[88]易娟,陈静,孙静,等.小白菊内酯对白血病K562细胞及其干细胞的作用[J].中国中药杂志,2010,35(2)：219-222.
[89]Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells [J]. Blood, 2007,110(13):4427-4435.
[90]Neelakantan S, Nasim S, Guzman et al. Aminoparthenolides as novel anti-leukemic agents:Discovery of the NF-kappa B inhibitor, DMAPT (LC-1) [J].Bioorg Med Chem Lett,2009,19 (15):4346-4354.
[91]Jin Y, Lu Z, Ding K, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells:inactivation of the NF-kappaB pathway and generation of reactive oxygen species [J].Cancer Res,2010,70(6): 2516-2527.
[92]查洁,张妍琰,王诗韵,等.Disulfiram联合Cu对淋巴瘤Raji细胞增殖与凋亡影响及其机制的探讨[J].中华肿瘤防治杂志,2012,19(2)：81-83.
[93]Xu B, Shi PC, Fombon IS, et al. Disulfiram/copper complex activated JNK/c-jun pathway and sensitised cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J].Blood Cells Mol Dis,2011,47(4):264-269.
[94]王诗韵,查洁,董慧娟,等.DC/Cu对急性髓系白血病干细胞增殖与凋亡影响及其机制的探讨[J].中华肿瘤防治杂志,2013,20(6)：411-415.
[95]Aguilar-Morante D, Morales-Garcia JA, Sanz-SanCristobal M, et al. Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8[J].PLoS One,2010,5(11):13879.
[96]Guzman L, Li X, Corbett CA, et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl,1,2,4-thiadiazoline,3,5 dione (TDZD-8) [J]. Blood,2007,110(13): 4436-4444.
[97]Birkenkamp KU, Geuqien M, Scjepers H, et al. Constitutive NF-kappa B DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway [J]. Leukemia,2004,18(1):103-112.
[98]高莹莹,胡亮杉,韩慧娟,等.NVP-BEZ235抑制CD34+CD38-急性髓系白血病干细胞的增殖和集落形成[J].中国实验血液学杂志,2013,21(2)：334-338.
[99]Cheung AM, Mak TW. PTEN in the haematopoietic system and its therapeutic indications[J]. Trends Mol Med,2006,12(11):503-505.
[1]平宝红,孟凡义.肿瘤多药耐药逆转研究现状[J].白血病,2000,9(5)：314-316.
[2]董颖,陈宝安,林果为.拓扑异构酶Ⅱ与白血病多药耐药[J].国外医学：输血及血液学分册,2000,23(3)：181-183.
[3]Konoplcva M, Tari AM, Estrov E, et al. Liposomal Bcl-2 antisense ol igonucleotides enhance proliferatio, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins[J]. Blood, 2000,95(12):3929-3938.
[4]Dean M, Fojo T, Bates S. Tumor stem cells and drug resistance [J]. Nat Rev Cancer,2005,5(4):275-284.
[5]王颖超,冯磊,殷楚云,等.THP-1细胞系白血病干细胞的检测、分选及鉴定[J].郑州大学学报(医学版),2013,48(2)：210-213.
[6]刘俊,张先平,蔡世忠,等.白血病K562细胞株中CD34+细胞群的分离及其生物学特征[J].中国生物制品学杂志,2013,26(1)：22-26.
[7]Ho MM, Hogge DE, Ling V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia[J].Exp Hemato,2008,36(4):433-442.
[8]Marques DS, Sandrini JZ, Boyle RT, et al. Relationships between multidrug resistance (MDR) and stem cell markers inhuman chronic myeloid leukemia cell lines [J].Leuk Res,2010,34(6):757-762.
[9]Merchant AA, Matusi W. Targeting hedgehog a cancer stem cell pathway [J].Clin Cancer Res,2010, 16(12):3130-3140.
[10]Qadir M, O' Loughlin KL, Fricke SM, et al. Cyclosporin A is a broad-spectrum multidrug resistance modulator[J]. Clin Cancer Res,2005, 11(6):2320-2326.
[11]Jurecekova J, Hatok J, Stefanikova A, et al. Targeting of Bcl-2 family proteins for treatment of acute leukaemia [J]. Gen Physiol Biophys,2011,30 Spec No:S3-S12.
[12]Del PG, Bruno A, Del PM, et al. Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia[J]. Curr Cancer Drug Targets,2008,8(3):207-222.
[13]van Stijn A, van der Pol MA, Kok A, et al. Differences between the CD34+ and CD34- blast compartments in apoptosis resistance in acute myeloid leukemia [J]. Haematologica,2003,88(5):497-508.
[14]Costello RT, Mallet F, Gauqler B, et al. Human acute myeloid leukemia CD34+/CD38-progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities[J]. Cancer Res,2000,60(16):4403-4411.
[15]Queiroz KC, Ruela-De-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells[J]. Oncogene,2010, 29(48):6314-6322.
[16]Kobune M, Takimoto R, Murase K, et al. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+leukemic cells [J]. Cancer Sci,2009, 100(5):948-955.
[17]Neering SJ, Bushnell T, Sozer S, et al. Leukemia stem cells in a genetically defined murine model of blast crisis CML [J]. Blood,2007,110(7): 2578-2585.
[18]Eyler CE, Rich JN. Survival of the fittest:cancer stem cells in therapeutic resistance and angiogenesis[J].Clin Oncol,2008,26(17): 2839-2845.
[19]Guo BW, Xiao QC, Qi RG, et al. Arsenic Trioxide overcomes cell adhesion-mediated drug res i stance through down-regulating the expression of beta(1)-integrin in K562 chronic myelogenous leukemia cell line[J].Leuk Lymphoma, 2010,51(6):1090-1097.
[20]何侃,于沛,邢海燕,等N-cadherin阳性白血病KG1a细胞系在G0期抵抗VP16杀伤的作用[J].中国实验血液学杂志,2011,19(5)：1102-1106.
[21]胡婕,张茵,马保根,等.雷公藤红素逆转K 562/A02细胞多药耐药的实验研究[J].实用癌症杂志,2011,26(3)：226-229.
[22]蔡讯,陈芳源,韩洁英,等.槲皮素逆转白血病细胞株HL-60/ADM多药耐药的研究[J].中华肿瘤杂志,2005,27(6)：326-329.
[23]王为光,于广晴,张国艳,等.槲皮素体外逆转K562/ADM耐药的研究[J].黑龙江医药科学,2011,34(2)：28-29.
[24]陈玉英,李静,胡建达,等.大黄素对HL-60/ADR耐药细胞多药耐药逆转作用的研究[J].中国实验血液学杂志,2013,21(6)：1413-1422.
[25]陈宝安,李静,程坚,等.汉防已甲素联合柔红霉素对K562/A02细胞株P21蛋白和P糖蛋白表达的影响[J].中国实验血液学杂志,2009,17(5)：1179-1182.
[26]曹渊,方悦,秦蓉,等.汉防已甲素预防裸鼠白血病多药耐药性形成的研究[J].健康研究,2013,33(5)：335-338.
[27]马海英,赵瑾瑶,金伟,等.川芎嗪对转基因多药耐药细胞K562/MDR耐药性的逆转作用[J].吉林大学学报(医学版),2009,35(4)：599-602.
[28]李菲,张荣艳,邢娟娟.三氧化二砷逆转白血病细胞多药耐药的作用及机制[J].山东医药,2008,48(25)：30-31.
[29]王婷,双跃荣,庄小捷.川芎嗪联合三氧化二砷逆转K562/ADM细胞多药耐药的实验研究[J].实用癌症杂志,2009,34(2)：121-124.
[30]张怡敏,董邦权,海文利,等.姜黄素对耐药细胞株K562/ADM的耐药逆转作用研究[J].细胞与分子免疫学杂志,2009,25(10)：958-962.
[31]盖晓东,历春,李倩,等.柴胡皂苷在体外对人白血病细胞株K562/ADM多药耐药性的逆转作用[J].中国病理生理杂志,2012,28(1)：76-80.
[32]赵早云.毛冬青甲素对白血病细胞K562/A02多药耐药蛋白P-170的影响[J].光明中医,2010,25(7)：1165-1166.
[33]许静,李瑞明, 肖希斌,等.木犀草素抑制白血病耐药株K562/A02的GST-π表达[J].今日药学,2012,22(1)：7-9.
[34]杨莉洁,赵挺,白庆咸,等.黄芩苷对白血病细胞耐药株逆转耐药效果及机制 研究[J].陕西医学杂志,2012,41(7)：775-778.
[35]黄望香,曾雪花,李翠霞,等.双氢青蒿素对白血病多药耐药K562/ADM细胞的逆转作用[J].医学理论与实践,2012,25(15)：1810-1812.
[36]田亮,刘娟,陈宝安,等.藤黄酸对白血病K562/A02细胞的耐药逆转作用[J].中国实验血液学杂志,2012,20(2)：252-257.
[37]秦小清,梁宇光,高洪志,等.五味子甲素对K562/ADR、HL60/ADR、MCF-7/ADR多药耐药逆转机制的研究[J].中国药理学通报,2011,27(3)：329-334.
[38]石倩倩,丁亚辉,祁瑞哲,等.小白菊内酯诱导耐药白血病细胞K562/ADR凋亡的研究[J].中国药理学通报,2012,28(12)：1736-1740.
[39]方凡夫,张亚妮,顾伟.蟾毒灵抑制人白血病多药耐药K562/VCR细胞株增殖的实验研究[J].中药新药与临床药理,2010,21(3)：213-215.
[40]胡美薇,张越峰,姚国丽.鸦胆子油乳抑制人白血病多药耐药K562/VCR细胞株增殖的实验研究[J].浙江实用医学,2012,17(5)：315-317.
[41]彭向前,杨培民,吴慧,等.半夏水提取液逆转多药耐药细胞系K562/A02耐药性的研究[J].齐鲁药事,2012,31(7)：385-387.
[42]李洁,刘盼盼.半枝莲逆转白血病细胞株K562/A02耐药性的实验研究[J].中医药导报,2012,18(5)：88-89.
[43]熊新,周远大.蟾蜍注射液逆转HL60/阿霉素细胞多药耐药的机制[J].南方医科大学学报,2012,32(3)：337-380.
[44]李秀军,严鲁萍,姚宇红.扶正祛邪中药复方含药血清抗白血病细胞HL60及HL60/VCR细胞的体外实验研究[J].广东医学,2012,33(7)：896-897.
[45]马武开,李玉莹,姚血明,等.白血病HL60/ADR细胞Mdrl、NF-κB的表达及解毒化瘀药的干预作用[J].西安交通大学学报,2011,32(5)：592-595.
[46]马武开,姚血明,唐芳,等.解毒化瘀药对白血病K562/A02耐药细胞mdrl耐药基因、核因子κB信号影响的研究[J].重庆医科大学学报,2011,36(8)：897-899.
[47]马武开,姚血明,王莹,等.解毒化瘀药含药血清对白血病HL60/ADR耐药细胞NF-κB信号靶向干预研究[J].中国实验方剂学杂志,2011,17(18)：154-157.
[48]廖斌,葛仁英,徐成波,等.中药复方君子汤对白血病细胞株K562/VCR耐药性的逆转作用[J].福建中医药大学学报,2011,21(4)：9-12.
[49]林潇,盛国良,孙付军,等.黄连解毒汤所含黄芩苷、京尼平苷对K562/ADM细胞多药耐药相关基因表达的影响[J].中药药理与临床,2012,28(6)：20-24.
[50]史哲新,杨向东,高宏,等.益气养阴法对微小残留白血病多药耐药相关因子的影响[J].天津中医药,2009,26(6)：453-454.
[51]李冬云,陈信义,侯丽,等.从痰瘀论治难治性白血病[J].中国中医基础理论杂志,2009,15(5)：365-367.
[52]李冬云,陈信义,许亚梅.难治性急性白血病研究现状与进展[J].现代生物医学进展,2007,7(8)：1239-1246.
[53]李冬云,陈信义,姜靖雯.复方浙贝颗粒研究现状与应用前景分析[J].中国药 物与临床,2009,9(2)：85-87.
[54]张寅,李冬云,田劭丹,等.复方浙贝颗粒配方伍用化疗治疗难治性急性白血病临床研究[J].河北中医药学报,2006,21(4)：9-11.
[55]李冬云,田劭丹,叶霈智,等.复方浙贝颗粒辅助化疗提高难治性急性白血病临床疗效研究[J].北京中医,2007,26(2)：70-72.
[56]李冬云,郑智,侯丽,等.复方浙贝药物血清抑制L1210/CDDP细胞增殖与诱导凋亡研究[J].现代生物医学进展,2009,9(13)：2413-2416.
[57]郑智,李冬云,陈信义.复方浙贝药物血清影响K562/A02细胞积聚外排功能和细胞凋亡研究[J].中国中西医结合杂志,2010,30(2)：170-173.
[58]郑智,李冬云,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤抑瘤率影响研究[J].当代医学,2010,16(1)：5-6.
[59]郑智,陈菊,李冬云,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤mdrl基因表达的影响[J].中西医结合学报,2009,7(8)：758-762.
[60]陈信义,郑智,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞凋亡及相关蛋白表达的影响[J].中国实验血液学杂志,2009,17(6)：1439-1442.
[61]郑智,侯丽,许亚梅,等.复方浙贝颗粒联合阿霉素影响K562/A02移植瘤细胞耐药相关酶表达研究[J].医学研究杂志,2009,38(12)：29-31.
[62]李冬云,郑智,侯丽,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞膜转运蛋白表达的影响.中国实验血液学杂志,2010,18(1)：1-4.
[1]Felipe Rico J, Has sane DC, Guzman ML. Acute myelogenous leukemia stem cells: From Bench to Bedside[J].Cancer Lett,2013,338(1):4-9.
[2]李冬云,田劭丹,叶霈智,等.复方浙贝颗粒辅助化疗提高难治性急性白血病临床疗效研究[J].北京中医,2007,26(2)：70-72.
[3]郑智,李冬云,陈信义.复方浙贝药物血清影响K562/A02细胞积聚外排功能和细胞凋亡研究[J].中国中西医结合杂志,2010,30(2)：170-173.
[4]陈信义,郑智,陈菊,等.复方浙贝颗粒联合阿霉素对K562/A02移植瘤细胞凋亡及相关蛋白表达的影响[J].中国实验血液学杂志,2009,17(6)：1439-1442.
[5]郑智,侯丽,许亚梅,等.复方浙贝颗粒联合阿霉素影响K562/A02移植瘤细胞耐药相关酶表达研究[J].医学研究杂志,2009,38(12)：29-31.
[6]张之南,沈悌.血液病诊断及疗效标准[M].第3版.北京：科学技术出版社,2007：103-116.
[7]陈运贤,丁倩.白血病治疗新靶点—白血病干细胞[J].新医学,2008,39(9)：613-614.
[8]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice[J]. Nature,1994, 367(6764):645-648.
[9]Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML) [J]. Blood, 2003,101(8):3142-3149.
[10]Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells [J]. Blood, 2005,106(2): 673-680.
[11]Ho MM, Hogge DE, Ling V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia [J].Exp Hemato,2008,36(4):433-442.
[12]Jurecekova J, Hatok J, Stefanikova A, et al. Targeting of Bcl-2 family proteins for treatment of acute leukaemia [J].Gen Physiol Biophys,2011,30 Spec No: S3-S12.
[13]Costello RT, Mallet F, Gauqler B, et al. Human acute myeloid leukemia CD34+/CD38-progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities[J]. Cancer Res,2000, 60(16):4403-4411.
[14]Jin L, LEE EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells[J].Cell Stem Cell,2009,5(1):31-42.
[15]Feuring-Buske M, Frankel AE, Alexander RL, et al. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to Primitive acute myeloid leukemia progenitors but spares normal progenitors[J]. Cancer Res,2002,62(6): 1730-1736.
[16]Frankel A, LiuJ S, Rizzieri D, etal. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia[J]. Leuk Lymphoma,2008,49(3):543-553.
[17]张砚君,李双静,姜琳琳,等IL-3-LDM融合蛋白对CD123+白血病细胞的靶向杀伤作用[J].中国肿瘤生物治疗杂志,2013,20(4)：391-397.
[18]Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial[J]. J Clin Oncol,2011,29(4): 369-377.
[19]Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells[J]. Blood,2001,98(8):2301-2307.
[20]Martelli AM, Nyakern M, TabelliniG, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia[J]. Leukemia,2006,20(6):911-928.
[21]陆荣. 白血病发病与骨髓微环境的关系[J].医学综述,2011,17(18)：2762-2765.
[22]Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells[J]. Blood,2005,105(11):4163-4169.
[23]Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells[J]. Blood,2007,110(13):4427-4435.
[24]Neelakantan S, Nasim S, Guzman et al. Aminoparthenolides as novel anti-leukemic agents:Discovery of the NF-kappa B inhibitor, DMAPT (LC-1) [J]. Bioorg Med Chem Lett,2009,19 (15):4346-4354.
[25]Birkenkamp KU, Geuqien M, Scjepers H, et al. Constitutive NF-kappa B DNA-binding activity n AML s frequently ediated by a Ras/PI3-K/PKB-dependent pathway [J].Leukemia,2004,18(1):103-112.
[26]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells[J]. Nature,2006, 441(7092):475-482.
[27]Cheung AM, Mak TW. PTEN in the haematopoietic system and its therapeutic indications [J]. Trends Mol Med,2006,12(11):503-505.
[28]Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemia stem cells [J]. Nat Med, 2006,12(10):1167-1174.
[29]Konopleva M, Tabe Y, Zeng Z, et al. Therapeutic targeting of microenvironmental interactions in leukemia:Mechanisms and approaches[J]. Drug Resist Updat,2009,12(4-5):103-113.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |