Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany;
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24326-24335. doi: 10.1073/pnas.2009078117. Epub 2020 Sep 14.
Kindlin-3 (K3)-mediated integrin adhesion controls homing and bone marrow (BM) retention of normal hematopoietic cells. However, the role of K3 in leukemic stem cell (LSC) retention and growth in the remodeled tumor-promoting BM is unclear. We report that loss of K3 in a mouse model of chronic myeloid leukemia (CML) triggers the release of LSCs from the BM into the circulation and impairs their retention, proliferation, and survival in secondary organs, which curbs CML development, progression, and metastatic dissemination. We found de novo expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CML-LSCs but not normal hematopoietic stem cells and this enabled us to specifically deplete K3 with a CTLA-4-binding RNA aptamer linked to a K3-siRNA (small interfering RNA) in CTLA-4 LSCs in vivo, which mobilized LSCs in the BM, induced disease remission, and prolonged survival of mice with CML. Thus, disrupting interactions of LSCs with the BM environment is a promising strategy to halt the disease-inducing and relapse potential of LSCs.
Kindlin-3 (K3) 介导的整合素黏附控制正常造血细胞的归巢和骨髓 (BM) 保留。然而，K3 在白血病干细胞 (LSC) 在重塑的肿瘤促进 BM 中的保留和生长中的作用尚不清楚。我们报告说，慢性髓系白血病 (CML) 小鼠模型中 K3 的缺失会触发 LSC 从 BM 释放到循环中，并损害它们在次级器官中的保留、增殖和存活，从而抑制 CML 的发展、进展和转移传播。我们发现 CML-LSC 上有新表达的细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4)，但正常造血干细胞上没有，这使我们能够在体内用与 K3-siRNA 相连的 CTLA-4 结合 RNA 适体特异性地耗尽 K3，从而动员 BM 中的 LSC，诱导疾病缓解，并延长 CML 小鼠的存活。因此，破坏 LSC 与 BM 环境的相互作用是阻止 LSC 诱导疾病和复发潜力的一种有前途的策略。
