Osteoblasts protect AML cells from SDF-1-induced apoptosis.
Osteoblasts protect AML cells from SDF-1-induced apoptosis.
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DOI：
10.1002/jcb.24755
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发表时间：
2014-06
影响因子：
4
通讯作者：
Hedin, Karen E.
中科院分区：
文献类型：
--
作者：
Kremer, Kimberly N.;Dudakovic, Amel;McGee-Lawrence, Meghan E.;Philips, Rachael L.;Hess, Allan D.;Smith, B. Douglas;van Wijnen, Andre J.;Karp, Judith E.;Kaufmann, Scott H.;Westendorf, Jennifer J.;Hedin, Karen E.
骨髓为急性髓性白血病（AML）细胞提供了一个保护环境，通常允许白血病干细胞在标准化疗方案中存活。靶向骨髓内的这些白血病干细胞对于预防复发至关重要。我们最近证明，骨髓中丰富的趋化因子SDF-1在AML细胞系和表达高水平受体CXCR4的患者样本中诱导细胞凋亡。在这里，我们表明骨髓内的成骨细胞谱系细胞亚群可以保护AML细胞免受细胞凋亡的影响，以响应自然存在于该位置的SDF-1。在共培养系统中，不同分化阶段的成骨细胞保护AML细胞系和患者分离株免受sdf -1诱导的凋亡。成骨细胞系MC3T3和W-20-17的分化通过细胞接触无关机制介导了这种保护作用。相比之下，骨髓来源的间充质细胞（成骨细胞的前体）通过依赖cxcr4的机制诱导AML细胞凋亡，并不能保护AML细胞免受外源性添加的SDF-1的影响。这些结果表明，在分化过程中的成骨细胞可以有效地抑制骨髓中表达cxcr4的AML细胞的sdf -1驱动的凋亡途径。靶向这种保护机制的药物可能通过增强骨髓微环境中sdf -1诱导的AML细胞凋亡，为治疗AML提供一种新的途径。
The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment.
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