Pharmacological Inhibition of NF-κB in Mesenchymal Stromal Cells Selectively Partitions Apoptosis-Inducing Factors in Their Microvesicles and Proliferation-Inducing Factors in Their Exosomes: Implications in the Management of Acute Myeloid Leukemia.

We previously showed that inhibition of the NF-κB signaling pathway in mesenchymal stromal cells (MSCs) (NKI-MSCs) induces quiescence in co-cultured hematopoietic stem cells (HSCs). This led us to investigate whether NKI-MSCs exert similar growth-inhibitory effects on leukemic cells. We found that both NKI-MSCs and their secretome induce cell cycle arrest in KG1a cells, a cell line of acute myeloid leukemia (AML) origin. Surprisingly, the extracellular vesicles (EVs) isolated from NKI-MSCs supported the proliferation of KG1a cells. This is perhaps the first report showing the opposite effects of MSCs and the EVs secreted by them. Further analysis revealed that microvesicles (MVs) from NKI-MSCs inhibited KG1a cell growth and induced apoptosis, whereas exosomes (Exos) supported proliferation. Our findings could have clinical implications. NKI-MVs, having apoptosis-inducing activity, could serve as an adjunct, off-the-shelf biologic to limit AML growth, enabling reduced-intensity chemotherapy in elderly patients and patients having co-morbidities. NF-κB inhibitors have been tried as chemotherapeutic agents for treating AML patients. However, systemic inhibition of NF-κB may also affect the bone marrow resident MSCs, which in turn could produce EVs supporting the proliferation of AML blasts. Our data could explain the inadequate clinical effectiveness of NF-κB inhibitors in treating AML, and also raise a concern for the systemic use of NF-κB inhibitors in the therapeutic regimen.