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

AI Article Synopsis

  • Kindlin-3 (K3) is crucial for the adhesion and retention of normal hematopoietic cells in the bone marrow, but its role in leukemic stem cells (LSCs) remains unclear.* -
  • In a study, loss of K3 in a mouse model of chronic myeloid leukemia (CML) caused LSCs to enter the bloodstream, reducing their growth and survival, which helped slow down CML development.* -
  • By targeting K3 using a CTLA-4-specific RNA aptamer in CML-LSCs, researchers were able to mobilize these cells from the bone marrow, achieving disease remission and extending the survival of affected mice.*

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533676PMC
http://dx.doi.org/10.1073/pnas.2009078117DOI Listing

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