Targeting Wnt pathway in mantle cell lymphoma-initiating cells.
Targeting Wnt pathway in mantle cell lymphoma-initiating cells.
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DOI：
10.1186/s13045-015-0161-1
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发表时间：
2015-06-06
影响因子：
28.5
通讯作者：
Samaniego F
中科院分区：
文献类型：
--
作者：
Mathur R;Sehgal L;Braun FK;Berkova Z;Romaguerra J;Wang M;Rodriguez MA;Fayad L;Neelapu SS;Samaniego F
套细胞淋巴瘤（MCL）是一种侵袭性和不可治愈的非霍奇金淋巴瘤。尽管最初进行了强烈的化疗，但高达50%的MCL病例通常以化疗耐药形式复发。我们假设最近发现的MCL起始细胞（MCL-ICs）是MCL复发和耐药的主要原因。癌症干细胞相关的途径，如Wnt，可能是它们维持和存活的原因。我们基于确定的标志物表达模式（CD 34-CD 3-CD 45 + CD 19-）从原代MCL细胞中分离MCL-IC，并研究Wnt途径表达。我们还测试了Wnt途径抑制剂在消除MCL-IC中的潜力。我们发现，MCL-IC对遗传毒性药物长春新碱、多柔比星和新批准的伯顿酪氨酸激酶（BTK）抑制剂伊曲替尼具有耐药性。我们证实了Wnt通路在MCL-IC中的差异上调。事实上，MCL-IC对Wnt通路抑制剂特别敏感。靶向β-连环蛋白-TCF 4与CCT 036477、iCRT 14或PKF 118 -310的相互作用优先消除了MCL-IC。我们的研究结果表明，Wnt信号传导对MCL-IC的维持和存活至关重要，有效的MCL治疗应旨在通过Wnt信号传导抑制剂消除MCL-IC。本文的在线版本（doi：10.1186/s13045-015-0161-1）包含补充材料，可供授权用户使用。
Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin’s lymphoma. Despite initial intense chemotherapy, up to 50 % of cases of MCL relapse often in a chemoresistant form. We hypothesized that the recently identified MCL-initiating cells (MCL-ICs) are the main reason for relapse and chemoresistance of MCL. Cancer stem cell-related pathways such as Wnt could be responsible for their maintenance and survival. We isolated MCL-ICs from primary MCL cells on the basis of a defined marker expression pattern (CD34-CD3-CD45+CD19-) and investigated Wnt pathway expression. We also tested the potential of Wnt pathway inhibitors in elimination of MCL-ICs. We showed that MCL-ICs are resistant to genotoxic agents vincristine, doxorubicin, and the newly approved Burton tyrosine kinase (BTK) inhibitor ibrutinib. We confirmed the differential up-regulation of Wnt pathway in MCL-ICs. Indeed, MCL-ICs were particularly sensitive to Wnt pathway inhibitors. Targeting β-catenin-TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs. Our results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors. The online version of this article (doi:10.1186/s13045-015-0161-1) contains supplementary material, which is available to authorized users.
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