Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia.
Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia.
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DOI：
10.4161/onci.20249
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发表时间：
2012-08-01
期刊：
影响因子：
7.2
通讯作者：
Heisterkamp N
中科院分区：
文献类型：
--
作者：
Feldhahn N;Arutyunyan A;Stoddart S;Zhang B;Schmidhuber S;Yi SJ;Kim YM;Groffen J;Heisterkamp N
尽管急性淋巴细胞白血病 (ALL) 的治愈率有所提高，但耐药性的产生和患者复发仍很常见。已知白血病细胞在药物治疗期间所处的环境可提供显着的生存益处。在这里，我们通过在基质存在的情况下培养小鼠 Bcr/Abl 阳性急性淋巴细胞白血病细胞，同时用中等剂量的两种不相关药物（法尼基转移酶抑制剂 lonafarnib 和酪氨酸激酶抑制剂 nilotinib）治疗它们来模拟这一过程。这导致培养物的细胞活力最初大幅降低并抑制细胞增殖。然而，几天后，细胞死亡停止，培养物变得耐药，使细胞分裂能够恢复。通过基因表达谱分析，我们发现耐药性的发展伴随着与一般炎症反应相关的基因（例如金属蛋白酶 MMP9）的大量转录上调。在尼罗替尼耐受的 ALL 细胞中，MMP9 蛋白水平和酶活性也有所增加。 p38、Akt 和 Erk 的激活与环境介导的耐药性 (EMDR) 的发展相关，Akt 和 Erk 抑制剂与尼洛替尼联合使用可降低细胞产生耐药性的能力。然而，p38 的抑制促进了尼罗替尼耐药性的增加。我们得出的结论是，ALL 细胞发生 EMDR 涉及许多细胞内途径的变化。因此，可以通过与具有不同靶点的其他药物同时治疗来避免对尼洛替尼等药物产生耐受性。
Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. Using gene expression profiling, we found that the development of drug resistance was accompanied by massive transcriptional upregulation of genes that are associated with general inflammatory responses such as the metalloproteinase MMP9. MMP9 protein levels and enzymatic activity were also increased in ALL cells that had become nilotinib-tolerant. Activation of p38, Akt and Erk correlated with the development of environment-mediated drug resistance (EMDR), and inhibitors of Akt and Erk in combination with nilotinib reduced the ability of the cells to develop resistance. However, inhibition of p38 promoted increased resistance to nilotinib. We conclude that development of EMDR by ALL cells involves changes in numerous intracellular pathways. Development of tolerance to drugs such as nilotinib may therefore be circumvented by simultaneous treatment with other drugs having divergent targets.
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影响因子：
50.3
作者：
Klemm L;Duy C;Iacobucci I;Kuchen S;von Levetzow G;Feldhahn N;Henke N;Li Z;Hoffmann TK;Kim YM;Hofmann WK;Jumaa H;Groffen J;Heisterkamp N;Martinelli G;Lieber MR;Casellas R;Müschen M
通讯作者：
Müschen M
c型凝集素的Dectin-2家族在免疫和稳态中。
影响因子：
3.8
作者：
Graham, Lisa M.;Brown, Gordon D.
通讯作者：
Brown, Gordon D.
影响因子：
51.1
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
5.4
作者：
Arce, I;Martínez-Muñoz, L;Fernández-Ruiz, E
通讯作者：
Fernández-Ruiz, E
影响因子：
158.5
作者：
Kantarjian, Hagop;Giles, Francis;Ottmann, Oliver G.
通讯作者：
Ottmann, Oliver G.