Co-expression of wild-type FLT3 attenuates the inhibitory effect of FLT3 inhibitor on FLT3 mutated leukemia cells.
Co-expression of wild-type FLT3 attenuates the inhibitory effect of FLT3 inhibitor on FLT3 mutated leukemia cells.
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DOI：
10.18632/oncotarget.10147
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Kiyoi H
中科院分区：
文献类型：
--
作者：
Chen F;Ishikawa Y;Akashi A;Naoe T;Kiyoi H
FLT 3突变在约30%的急性髓细胞白血病（AML）患者中发现，并与预后不良相关。几种FLT 3抑制剂正在进行研究，但其临床疗效低于预期，并且已经证明了对FLT 3抑制剂的几种耐药机制。尽管大多数携带FLT 3突变的AML细胞共表达野生型（Wt）-FLT 3，但尚未完全了解Wt-FLT 3表达如何与FLT 3抑制剂耐药性相关。在这项研究中，我们阐明了FL依赖性Wt-FLT 3激活降低FLT 3抑制剂抑制作用的耐药机制。我们证明了FL刺激在体外和体内都比单独的表达mu-FLT 3的细胞更强烈地降低了FLT 3抑制剂对Wt-和mu-FLT 3共表达细胞的生长抑制作用。还证实FL损害FLT 3抑制剂对原代AML细胞的抗白血病作用。我们阐明了FL主要通过激活Wt-FLT 3而不是突变的FLT 3来阻碍FLT 3抑制剂在Wt和ITD-FLT 3共表达细胞中的抑制作用。此外，FL诱导的Wt-FLT 3-MAPK轴激活是导致耐药的主要途径，而Wt-FLT 3的糖基化也是FL依赖性激酶激活和对FLT 3抑制剂耐药的关键。因此，我们阐明了共表达Wt-FLT 3在对FLT 3抑制剂耐药中的重要性。这些发现为我们提供了重要的临床应用和新的策略，以改善FLT 3抑制剂的临床结果的影响。
FLT3 mutation is found in about 30% of acute myeloid leukemia (AML) patients and is associated with a poor prognosis. Several FLT3 inhibitors are undergoing investigation, while their clinical efficacies were lower than expected and several resistant mechanisms to FLT3 inhibitors have been demonstrated. Although most AML cells harboring FLT3 mutation co-express wild-type (Wt)-FLT3, it is not fully understood how Wt-FLT3 expression is associated with the resistance to FLT3 inhibitors. In this study, we elucidated a resistant mechanism by which FL-dependent Wt-FLT3 activation reduced inhibitory effects of FLT3 inhibitors. We demonstrated that FL-stimulation much more strongly reduced growth inhibitory effects of FLT3 inhibitors on Wt- and mutant-FLT3 co-expressing cells than sole mutant-FLT3 expressing cells both in vitro and in vivo. It was also confirmed that FL impaired the anti-leukemia effects of FLT3 inhibitors on primary AML cells. We elucidated that FL impeded the inhibitory effects of FLT3 inhibitors mainly through the activation of Wt-FLT3, but not mutated FLT3, in the Wt- and ITD-FLT3 co-expressing cells. Furthermore, FL-induced activation of Wt-FLT3-MAPK axis was the dominant pathway for the resistance, and the glycosylation of Wt-FLT3 was also vital for FL-dependent kinase activation and following resistance to FLT3 inhibitors. Thus, we clarified the importance of co-expressing Wt-FLT3 in resistance to FLT3 inhibitors. These findings provide us with important implications for clinical application and new strategies to improve clinical outcomes of FLT3 inhibitors.
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影响因子：
2.1
作者：
Grunwald, Michael R.;Levis, Mark J.
通讯作者：
Levis, Mark J.
影响因子：
20.3
作者：
Ben-Batalla, Isabel;Schultze, Alexander;Loges, Sonja
通讯作者：
Loges, Sonja
影响因子：
64.8
作者：
Straussman, Ravid;Morikawa, Teppei;Shee, Kevin;Barzily-Rokni, Michal;Qian, Zhi Rong;Du, Jinyan;Davis, Ashli;Mongare, Margaret M.;Gould, Joshua;Frederick, Dennie T.;Cooper, Zachary A.;Chapman, Paul B.;Solit, David B.;Ribas, Antoni;Lo, Roger S.;Flaherty, Keith T.;Ogino, Shuji;Wargo, Jennifer A.;Golub, Todd R.
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Golub, Todd R.
影响因子：
20.3
作者：
Shiotsu, Yukimasa;Kiyoi, Hitoshi;Naoe, Tomoki
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Naoe, Tomoki
影响因子：
8
作者：
Kiyoi, H;Ohno, R;Naoe, T
通讯作者：
Naoe, T