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miRNA-Mediated Rescue of NK Cell Cytotoxicity Against Drug-Resistant Quiescent Leukemia Stem Cells


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During the period covered by this report, we found that sustained pre-miR-155 expression partially rescued the inhibitory effect of the bone marrow mesenchymal stroma cell (MSC) conditioned medium (CM) on human NK cell cytotoxic activity against CD34+ blast crisis CML (CML-BC) stem and progenitor cells. Similar results were obtained using NK cells from wt and miR-155 transgenic (tg) mice and BCR-ABL1-expressing mouse 32Dcl3 myeloid precursors. Mechanistically, we found that FAS and DR5, but not NK-G2D, ligands are overexpressed in primary BCR-ABL1 transgenic mouse stem/progenitor cells, and that tg miR-155 NK cells express TRIAL and FAS Ligand at high levels. Moreover, we gathered evidence showing that miR-155 tg NK-mediated killing of BCR-ABL1+ cells is FAS dependent. Interestingly, we also found that overexpression of pre-MiR-155 leads to downregulation of premiR-300 levels, suggesting the existence of a negative feedback loop. We will continue investigating the pre-miR155-dependent mechanism leading to restored NK cell cytotoxic activity toward leukemic stem cells and determine whether sustained pre-miR-155 combined with miR-300 inhibition will enhance killing of CML quiescent stem cells. Thus, the project goals and SOW remain the same for the approved no-cost extension period.



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