miRNA-Mediated Rescue of NK Cell Cytotoxicity Against Drug-Resistant Quiescent Leukemia Stem Cells
Abstract
Chronic myelogenous leukemia (CML) is a stem cell-derived white cell blood disorder clinically manageable with tyrosine kinase inhibitors (TKIs) like Gleevec. However, innate and acquired drug-resistance remains a major therapeutic challenge. Importantly, TKI-based therapies are not effective against CML leukemic stem cells (LSCs). Moreover, persistence of drug-resistant LSCs is a characteristic of other myeloid malignancies (e.g., acute myeloid leukemia [AML] and myelodysplatic syndromes [MDS]) with dismal outcome. Thus, the identification of therapies targeting LSCs is of primary importance for eradication of these and other deadly cancers. Natural killer (NK) cells are immune cells that represent the human first line defense against cancer. They are capable of and prefer to kill LSCs and undifferentiated cancer cells; however, NK cell numbers and activity are impaired in almost all types of cancers including CML, and it gets restored in a tiny cohort of patients in long-lasting remission after therapy discontinuation. Our preliminary experiments indicate that other bone marrow (BM) cell types and the low oxygen tension inhibit NK cell function by subverting the balance between small ribonucleic acid molecules, termed microRNAs (miRNAs), with NK cell activatory and inhibitory function. Among these, levels of the activator miRNA-155 go down, whereas those of the inhibitor miRNA-300 go up in the NK cell living in the leukemic BM niche in the proximity of the LSCs. We also provided evidence that activated NK cells can kill CML LSCs capable of re-initiating blood cancer. The aim of this proposal is to gather a series of lab evidences supporting the key role played by these microRNAs and to demonstrate that skewing the miRNA balance toward activatory signals by using viruses, called lentiviruses, that render NK cells always active by producing lots of activatory miRNA-155 and are also instructed to produce a molecule that binds the inhibitory miR-300 and kill its inhibitory activity. We plan to use these lentiviruses to modify and activate NK-92 cells, and then use these cells in immunodeficient mice affected by CML. We expect that the superactivated NK-92 cells will efficiently kill the majority of LSCs, thereby leading to cure CML at its stem cell origin. The final goal of this study is to identify a CML immunotherapy that, in combination with TKIs, will efficiently kill leukemia stem cells. The successful completion of this study will serve as proof-of-concept for developing miRNA-based NK cell immunotherapies for stem cell-derived tumors with dysfunctional NK cells; hence, the strong significance of these studies for basic and bench-to-bed cancer research. Notably, CML and other myeloid malignancies (e.g., AML, MDS) occur at higher incidence in Veteran patients and are associated to exposure during military Service to hazardous mutagenic (e.g., ionizing radiation) environment. Thus, new therapeutic approaches aimed at eradicating myeloid leukemias at stem cell level will benefit active military personnel as well as Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910166
Entities
People
- Danilo Perrotti
Organizations
- United States Army
- University of Maryland, Baltimore