Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function
Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function
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DOI：
10.1073/pnas.1301838110
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发表时间：
2013-06-18
影响因子：
11.1
通讯作者：
Ong, S. Tiong
中科院分区：
文献类型：
--
作者：
Lim, Sharon;Saw, Tzuen Yih;Ong, S. Tiong
慢性粒细胞白血病在慢性期对靶向致癌融合蛋白BCR-ABL 1的治疗反应良好，但在进展到急变（BC）后对治疗有抗性。BC的特征在于粒细胞巨噬细胞祖细胞（GMP）中的β-连环蛋白信号传导升高，这使得该群体能够充当白血病干细胞（LSC）并充当耐药性的储存库。由于正常造血干细胞（HSC）和LSC依赖于β-连环蛋白信号传导进行自我更新，因此特异性靶向BC的策略将需要鉴定能够区分BC LSC和正常HSC中的自我更新的可药物化因子。在这里，我们表明，MAP激酶相互作用的丝氨酸/苏氨酸激酶（MNK）-真核翻译起始因子4 E（eIF 4 E）轴在BC GMP中过表达，但在正常的HSC中没有，并且MNK激酶依赖的eIF 4 E在丝氨酸209处的磷酸化激活BC GMP中的β-连环蛋白信号传导。从机制上讲，eIF 4 E过表达和磷酸化导致β-连环蛋白蛋白合成增加，而MNK依赖性eIF 4 E磷酸化是β-连环蛋白核转位和激活所必需的。因此，我们发现一组小分子MNK激酶抑制剂在体外和体内阻止eIF 4 E磷酸化、β-连环蛋白活化和BC LSC功能。我们的研究结果确定了MNK-eIF 4 E轴作为BC自我更新的特异性和关键调节因子，并表明MNK激酶的药理学抑制可能在BC慢性髓性白血病中具有治疗作用。
Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated beta-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on beta-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates beta-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased beta-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of beta-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, beta-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.