Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches
Menée à l'aide d'un modèle murin de leucémie myéloïde chronique, cette étude démontre que la perte d'expression de la kindline-3 déclenche la libération dans la circulation sanguine de cellules souches leucémiques de la moelle osseuse et freine la progression de la maladie en altérant leur rétention, leur prolifération et leur survie dans les organes secondaires
Current leukemia treatments focus on targeting leukemic cells and neglect the influence of the malignant BM environment, which is modified to nurture and protect LSCs. By abrogating K3-mediated integrin adhesion of LSCs to BM niches, either through genetics or an LSC-specific RNA aptamer-mediated K3-siRNA delivery, we impaired integrin-mediated niche retention of LSCs, slowed down the course of leukemia in vivo, and prolonged the survival of mice suffering from CML. Therefore, delivering K3-depleting compounds via tumor-specific surface receptors represents a strategy to abolish the function of multiple integrin classes on LSCs and interactions with numerous niche components at once.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.We confirm that the data supporting the findings of this study are available within the article and SI Appendix or in public resources (Microarray Innovations in Leukemia Study; National Center for Biotechnology Information Gene Expression Omnibus [GSE13159]).