Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency.
Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency.
复制标题
DOI：
10.1038/onc.2015.456
复制
发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Voena C
中科院分区：
文献类型：
--
作者：
Ceccon M;Merlo MEB;Mologni L;Poggio T;Varesio LM;Menotti M;Bombelli S;Rigolio R;Manazza AD;Di Giacomo F;Ambrogio C;Giudici G;Casati C;Mastini C;Compagno M;Turner SD;Gambacorti-Passerini C;Chiarle R;Voena C
大多数间变性大细胞淋巴瘤（ALCL）病例携带产生融合蛋白NPM-ALK的t（2;5; p23;q35）。NPM-ALK激酶活性失调驱动支持淋巴瘤细胞恶性转化的几种途径。我们发现在ALK重排的ALCL细胞系中，NPM-ALK以等量分布在细胞质和细胞核之间。只有细胞质部分在细胞系和原发性ALCL中具有催化活性，而细胞核部分由于与NPM 1异源二聚化而无活性。因此，约50%的NPM-ALK没有活性，并作为NPM-ALK/NPM 1异二聚体被隔离在细胞核中。通过NPM基因敲除或敲低使NPM-ALK过表达或重新定位于细胞质，导致ERK 1/2通过ATM/Chk 2和γ H2 AX介导的DNA损伤反应增加磷酸化和细胞死亡。值得注意的是，对ALK酪氨酸激酶抑制剂（TKI）耐药的人NPM-ALK扩增细胞系在停药后由于ERK 1/2过度活化而发生细胞凋亡。总之，这些发现表明过量的NPM-ALK活化和信号传导通过致癌应激反应诱导细胞凋亡。暂停ALK TKI治疗的“休药期”可能代表通过NPM-ALK扩增产生耐药性的细胞的治疗选择。
Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK. NPM-ALK deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive due to heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or re-localization of NPM-ALK to the cytoplasm by NPM genetic knock-out or knock-down caused ERK1/2 increased phosphorylation and cell death through the engagement of an ATM/Chk2 and γH2AX mediated DNA damage response. Remarkably, human NPM-ALK amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A “drug holiday” where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.