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Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches.

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Krenn,  Peter William
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Krenn, P. W., Koschmieder, S., & Fässler, R. (2020). Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches. Proceedings of the National Academy of Sciences of the United States of America, 117(39), 24326-24335. doi:10.1073/pnas.2009078117.


Cite as: http://hdl.handle.net/21.11116/0000-0007-8281-3
Abstract
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.