The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells.
The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells.
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DOI：
10.1038/bcj.2011.16
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发表时间：
2011-05
影响因子：
12.8
通讯作者：
Naoe, T.
中科院分区：
文献类型：
--
作者：
Kuwatsuka, Y.;Minami, M.;Minami, Y.;Sugimoto, K.;Hayakawa, F.;Miyata, Y.;Abe, A.;Goff, D. J.;Kiyoi, H.;Naoe, T.
在 Ph 阳性 (Ph+) 白血病中，静止细胞状态是对 BCR-ABL 激酶抑制剂伊马替尼产生耐药性的原因之一。为了检查静息引起的耐药机制以及雷帕霉素抑制剂依维莫司的哺乳动物靶标对此类耐药群体的影响，我们使用 Ph+ 急性淋巴细胞白血病患者细胞连续异种移植到 NOD/SCID/IL2rγnull (NOG) 小鼠中。与 CD34+CD38+ 和 CD34− 群体相比，白血病小鼠的脾细胞在 CD34+CD38− 群体中显示出更高比例的慢周期 G0 细胞。离体伊马替尼治疗后，在 CD34+CD38− 群体中观察到的残留细胞多于其他群体。尽管慢周期G0细胞尽管存在BCR-ABL和CrkL去磷酸化，但对伊马替尼不敏感，但与依维莫司联合治疗可诱导大量细胞死亡，包括CD34+CD38−群体的细胞死亡，同时伴有p70-S6 K去磷酸化和MCL-1表达减少。采用伊马替尼和依维莫司体内联合治疗的白血病非肥胖糖尿病/严重联合免疫缺陷 (NOD/SCID) 小鼠系统显示肿瘤负荷减少，包括 CD34+ 细胞。这些结果表明，依维莫司治疗可以克服 Ph+ 白血病中由于静止而对伊马替尼的耐药性。
In Ph-positive (Ph+) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph+ acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγnull (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G0 cells in the CD34+CD38− population compared with the CD34+CD38+ and CD34− populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34+CD38− population than in the other populations. Although slow-cycling G0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34+CD38− population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34+ cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph+ leukemia due to quiescence.
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影响因子：
82.9
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
通讯作者：
Fruman, David A.
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
DOI：
10.1073/pnas.0400063101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Mohi, MG;Boulton, C;Neel, BG
通讯作者：
Neel, BG
影响因子：
20.3
作者：
Holyoake, T;Jiang, XY;Eaves, A
通讯作者：
Eaves, A
影响因子：
20.3
作者：
Cullion, Kathleen;Draheim, Kyle M.;Kelliher, Michelle A.
通讯作者：
Kelliher, Michelle A.