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）介导的整联蛋白粘附控制正常造血细胞的归巢和骨髓（BM）保留。然而，K3在重塑肿瘤的BM中在白血病干细胞（LSC）保留和生长中的作用尚不清楚。我们报告说，在慢性粒细胞白血病（CML）小鼠模型中K3的丢失会触发LSCs从BM释放进入循环系统，并损害其在次器官中的保留，增殖和存活，从而抑制CML的发生，发展和转移。传播。我们在CML-LSC上发现了细胞毒性T淋巴细胞相关抗原4（CTLA-4）的从头表达，但在正常的造血干细胞上却没有表达，这使我们能够通过与K3连接的CTLA-4结合RNA适体来特异性消耗K3。 siRNA对CTLA-4（小干扰RNA）⁺体内的LSC可以动员BM中的LSC诱导疾病的缓解，并延长CML小鼠的生存期。因此，破坏LSC与BM环境的相互作用是一种有希望的策略，可以阻止LSC的疾病诱发和复发潜能。