Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs.
Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs.
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DOI：
10.1084/jem.20140131
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发表时间：
2014-09-22
期刊：
影响因子：
--
通讯作者：
Bhatia M
中科院分区：
文献类型：
--
作者：
Boyd AL;Campbell CJ;Hopkins CI;Fiebig-Comyn A;Russell J;Ulemek J;Foley R;Leber B;Xenocostas A;Collins TJ;Bhatia M
原始白血病细胞的空间定位仅限于与其正常对应物共享的小生境，并且它们保留这些小生境的占用的能力与正常HSPC相媲美。异基因造血干细胞移植（HSCT）是目前治疗急性髓系白血病（AML）的主要策略。然而，治疗相关的发病率限制了HSCT使用的患者普遍性，并且白血病干细胞（LSC）在骨髓（BM）保护区内的存活继续导致高复发率。尽管LSC微环境的重要性越来越受到重视，但LSC是否优先在正常HSC小生境中生长，或者它们的小生境要求是否更混杂，仍然没有得到解决。在这里，我们提供了功能性证据，证明表型原始人AML细胞的空间定位仅限于与正常对应细胞共享的生态位元件，并且它们启动和保持这些生态位占据的内在能力可以与健康的造血干细胞和祖细胞相媲美。（HSPC）。当在竞争性BM再增殖试验中受到挑战时，原代人白血病起始细胞（L-IC）可以以细胞剂量依赖性方式持续优于HSPC的BM生态位占用，最终损害长期L-IC更新和随后的白血病起始能力。这种方法的有效性可以通过使用苦参碱诱导的已建立的白血病从BM的动员来证明，这有助于用移植的HSPC替换BM小生境。这些发现确定了原始白血病细胞的功能脆弱性，并表明这些新的移植技术的临床开发应集中在解离L-IC-生态位相互作用，以改善HSCT期间与健康HSPC的竞争性替代，从而提高患者的生存率。
Spatial localization of primitive leukemic cells is restricted to niches shared with their normal counterparts, and their ability to retain occupancy of these niches is rivaled by normal HSPCs. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC–niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients.
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