Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy
Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy
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DOI：
10.1182/blood-2012-12-475483
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发表时间：
2013-06-13
期刊：
影响因子：
20.3
通讯作者：
Sipkins, Dorothy A.
中科院分区：
文献类型：
--
作者：
Boyerinas, Benjamin;Zafrir, Maya;Sipkins, Dorothy A.
如果恶性细胞处于休眠状态，它们可以逃避细胞毒性剂的死亡。宿主微环境在癌症进展中起着重要作用，但小生境如何控制癌细胞休眠却知之甚少。我们发现骨桥蛋白（OPN）是成骨细胞分泌的一种细胞外基质分子，它可以将白血病原始细胞锚在支持肿瘤休眠的解剖位置。我们证明，急性淋巴细胞白血病（ALL）细胞在体外特异性粘附OPN，并在体内定位于骨内膜龛时分泌OPN。使用活体显微镜对异种移植小鼠的颅骨骨髓（BM）进行成像研究，我们发现骨桥蛋白在骨髓内休眠肿瘤细胞附近高度表达。抑制OPN-信号传导轴显著增加白血病细胞Ki-67增殖指数，并导致治疗小鼠的肿瘤负荷增加两倍。此外，使用细胞周期依赖性Ara-C化疗在白血病小鼠中产生微小残留病（MRD），我们表明OPN中和与Ara-C协同作用以减少可检测的BM MRD。总之，这些数据表明ALL与恶性BM内的细胞外OPN相互作用，并且这种相互作用诱导白血病原始细胞的细胞周期退出，保护它们免受细胞毒性化疗的影响。
Malignant cells may evade death from cytotoxic agents if they are in a dormant state. The hostmicroenvironment plays important roles in cancer progression, but how niches might control cancer cell dormancy is little understood. Here we show that osteopontin (OPN), an extracellular matrix molecule secreted by osteoblasts, can function to anchor leukemic blasts in anatomic locations supporting tumor dormancy. We demonstrate that acute lymphoblastic leukemia (ALL) cells specifically adhere to OPN in vitro and secrete OPN when localized to the endosteal niche in vivo. Using intravital microscopy to perform imaging studies of the calvarial bone marrow (BM) of xenografted mice, we show that OPN is highly expressed adjacent to dormant tumor cells within the marrow. Inhibition of the OPN-signaling axis significantly increases the leukemic cell Ki-67 proliferative index and leads to a twofold increase in tumor burden in treated mice. Moreover, using cell-cycle-dependent Ara-C chemotherapy to produce minimal residual disease (MRD) in leukemic mice, we show that OPN neutralization synergizes with Ara-C to reduce detectable BM MRD. Taken together, these data suggest that ALL interacts with extracellular OPN within the malignant BM, and that this interaction induces cell cycle exit in leukemic blasts, protecting them from cytotoxic chemotherapy.