Reduction of leukemic burden via bone-targeted nanoparticle delivery of an inhibitor of C-chemokine (C-C motif) ligand 3 (CCL3) signaling.
Reduction of leukemic burden via bone-targeted nanoparticle delivery of an inhibitor of C-chemokine (C-C motif) ligand 3 (CCL3) signaling.
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DOI：
10.1096/fj.202000938rr
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Frisch BJ
中科院分区：
文献类型：
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作者：
Ackun-Farmmer MA;Soto CA;Lesch ML;Byun D;Yang L;Calvi LM;Benoit DSW;Frisch BJ
白血病是一种具有挑战性的疾病，部分原因是白血病细胞与骨髓微环境（BMME）之间的相互作用对疾病进展起着重要作用。研究表明，白血病细胞分泌c趋化因子（C-C基序）配体3 (CCL3)，破坏BMME，导致造血功能丧失，支持白血病细胞存活和增殖。本研究利用表达易位产物BCR/ABL和Nup98/HoxA9的原细胞危象性慢性髓性白血病（bcCML）小鼠模型来确定CCL3在BMME调控中的作用。来源于CCL3 - / -小鼠的白血病细胞被证明可以在正常的BMME中最小程度地植入，从而证明CCL3信号对于再现bcCML疾病是必要的。进一步分析显示bcCML模型中BMME的造血功能受到破坏。为了挽救改变的BMME，研究人员使用骨靶向纳米颗粒（NP）递送CCL3受体C-C趋化因子受体5型（CCR5）抑制剂Maraviroc，对CCL3信号的治疗性抑制进行了研究。np介导的马拉韦洛克递送部分恢复了BMME，显著降低了白血病负担，提高了生存率。总之，我们的研究结果表明，通过CCR5拮抗剂抑制CCL3是一种潜在的治疗方法，可以恢复正常的造血功能，并减轻BMME内的白血病负担。
Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3−/− mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.