CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells.
CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells.
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DOI：
10.1186/1756-8722-7-29
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发表时间：
2014-03-31
影响因子：
28.5
通讯作者：
Zöller M
中科院分区：
文献类型：
--
作者：
Erb U;Megaptche AP;Gu X;Büchler MW;Zöller M
阻断CD 44被认为是消除白血病起始细胞的治疗选择。然而，抗panCD 44可干扰造血。因此，我们探索了CD 44变体同种型（CD 44 v）特异性抗体是否可以抑制白血病生长而不攻击造血。作为模型，我们使用CD 44 v10转染的EL 4胸腺瘤细胞（EL 4-v10）。静脉应用EL 4/EL 4-v10后，评价抗panCD 44和抗CD 44 v10的治疗效果。离体和体外研究评价了抗panCD 44和抗CD 44 v10以及EL 4和EL 4-v10对与骨髓基质细胞共培养的造血干细胞（HSC）的影响，重点关注粘附、迁移、细胞周期进展和抗凋亡性。腹腔注射的EL 4-v10在骨髓和脾脏中生长。抗panCD 44和更明显的抗CD 44 v10延长了生存时间。与抗panCD 44相比，抗CD 44 v10的更高疗效不依赖于更强的抗体依赖性细胞毒性或促进EL 4-v10凋亡。相反，EL 4与HSC小生境嵌入竞争。这对由基质提供的静止和凋亡保护信号有影响。抗panCD 44也比EL 4更有效地影响HSC在骨髓基质中的包埋。EL 4-v10通过捕获骨桥蛋白在骨髓基质上迁移，不干扰或微弱干扰HSC的粘附。抗CD 44 v10也不影响HSC -骨髓基质串扰。抗panCD 44和抗CD 44 v10的治疗作用基于刺激抗体依赖性细胞毒性。抗CD 44 v10的优势部分是由于阻断了CD 44 v10刺激的骨桥蛋白表达，这可能会将HSC赶出小生境。然而，抗CD 44 v10的优势的主要原因依赖于EL 4-v10或抗CD 44 v10均不严重干扰HSC -基质细胞相互作用，而另一方面，HSC -基质细胞相互作用受EL 4和抗panCD 44影响。抗panCD 44干扰HSC包埋在成骨龛中削弱了其对EL 4的治疗作用。因此，只要白血病细胞表达CD 44 v同种型，应避免使用抗panCD 44的治疗，而应使用CD 44 v特异性抗体。
A blockade of CD44 is considered a therapeutic option for the elimination of leukemia initiating cells. However, anti-panCD44 can interfere with hematopoiesis. Therefore we explored, whether a CD44 variant isoform (CD44v)-specific antibody can inhibit leukemia growth without attacking hematopoiesis. As a model we used CD44v10 transfected EL4 thymoma cells (EL4-v10). The therapeutic efficacy of anti-panCD44 and anti-CD44v10 was evaluated after intravenous application of EL4/EL4-v10. Ex vivo and in vitro studies evaluated the impact of anti-panCD44 and anti-CD44v10 as well as of EL4 and EL4-v10 on hematopoietic stem cells (HSC) in cocultures with bone marrow stroma cells with a focus on adhesion, migration, cell cycle progression and apoptosis resistance. Intravenously injected EL4-v10 grow in bone marrow and spleen. Anti-panCD44 and, more pronounced anti-CD44v10 prolong the survival time. The higher efficacy of anti-CD44v10 compared to anti-panCD44 does not rely on stronger antibody-dependent cellular cytotoxicity or on promoting EL4-v10 apoptosis. Instead, EL4 compete with HSC niche embedding. This has consequences on quiescence and apoptosis-protecting signals provided by the stroma. Anti-panCD44, too, more efficiently affected embedding of HSC than of EL4 in the bone marrow stroma. EL4-v10, by catching osteopontin, migrated on bone marrow stroma and did not or weakly interfere with HSC adhesion. Anti-CD44v10, too, did not affect the HSC – bone marrow stroma crosstalk. The therapeutic effect of anti-panCD44 and anti-CD44v10 is based on stimulation of antibody-dependent cellular cytotoxicity. The superiority of anti-CD44v10 is partly due to blocking CD44v10-stimulated osteopontin expression that could drive HSC out of the niche. However, the main reason for the superiority of anti-CD44v10 relies on neither EL4-v10 nor anti-CD44v10 severely interfering with HSC – stroma cell interactions that, on the other hand, are affected by EL4 and anti-panCD44. Anti-panCD44 disturbing HSC embedding in the osteogenic niche weakens its therapeutic effect towards EL4. Thus, as far as leukemic cells express CD44v isoforms, the therapeutic use of anti-panCD44 should be avoided in favor of CD44v-specific antibodies.
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影响因子：
3.5
作者：
Jacobs PP;Sackstein R
通讯作者：
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作者：
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