| Myeloid stem cells are blood cell progenitors that reside and develop in the bone marrow. Upon maturation, these cells are released into the circulation as either mature neutrophils or monocytes that develop into tissue macrophages. Both cell types are professional phagocytes that are critical to immune functions. During infection responses, neutrophils rapidly migrate to sites of infection, kill bacteria and then die, whereas macrophages devour the dead neutrophils and bacterial debris. Importantly, disruption of myeloid differentiation leads to myelogenous leukemia's that are characterized by dysregulated expansions of myeloid progenitors that can result in deficient neutrophil and macrophage production. However, over-activation of phagocytes in the inflammatory response can also have devastating effects, since this can lead to aberrant inflammatory conditions such as Rheumatoid Arthritis. Thus, identifying factors that regulate myeloid cell growth is important for the discovery of new drug therapies to treat dysregulated myeloid development and/or functional activation. Recent studies have suggested that a novel Ca2+/calmodulin-dependent protein kinase (CaMK) cascade plays a significant role in neutrophil proliferation and functional activation. In this study, inhibitors that block CaMK activity were used to test for possible effects on the growth and functional activation of myeloid progenitor models. Our results demonstrate that inhibitors can not only inhibit the growth responses of myeloid progenitors but also induce them to differentiate into mature macrophages. Our studies suggest that CaMK inhibitors may provide clinically relevant means of regulating CaMK activities that may be used to control the expansion and function of human myeloid stem cells. |
