Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA.
Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
FASEB J. 2021 Apr;35(4):e21402. doi: 10.1096/fj.202000938RR.
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.
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基质微环境（BMME）之间的相互作用，这些相互作用显著促进了疾病的进展。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，并支持白血病细胞的存活和增殖。在这项研究中，使用表达易位产物 BCR/ABL 和 Nup98/HoxA9 的慢性髓系白血病急变期（bcCML）的小鼠模型来确定 CCL3 在 BMME 调节中的作用。从 CCL3 小鼠中分离的白血病细胞在正常的 BMME 中最小程度地植入，从而证明 CCL3 信号对于重现 bcCML 疾病是必要的。进一步的分析表明，bcCML 模型中的 BMME 内造血功能紊乱。为了挽救改变的 BMME，使用骨靶向纳米颗粒（NP）来递送 Maraviroc，一种 C-C 趋化因子受体 5（CCR5）的抑制剂，来研究 CCL3 信号的治疗抑制作用，CCR5 是 CCL3 的受体。NP 介导的 Maraviroc 递送部分恢复了 BMME，显著降低了白血病负担，并提高了生存率。总的来说，我们的结果表明，通过 CCR5 拮抗抑制 CCL3 是一种潜在的治疗方法，可以恢复正常的造血功能，并减少 BMME 中的白血病负担。
