Gelsolin Induces Promonocytic Leukemia Differentiation Accompanied by Upregulation of p21CIP1

Tumor suppressor genes have received much attention for their roles in the development of human malignancies.Gelsolin has been found to be down-regulated in several types of human cancers, including leukemias. It is,however, expressed in macrophages, which are the final differentiation derivatives for the monocytic myeloidlineage, implicating this protein in the differentiation process of such cells. In order to investigate the role ofgelsolin in leukaemic cell differentiation, stable clones over-expressing ectopic gelsolin, and a control clone wereestablished from U937 leukaemia cells. Unlike the control cells, both gelsolin-overexpressing clones displayedretarded growth, improved monocytic morphology, increased NADPH and NSE activities, and enhanced surfaceexpression of the β-integrin receptor, CD11b, when compared with the parental U937 cells. Interestingly, RTPCRand western blot analysis also revealed that gelsolin enhanced p21CIP1 mRNA and protein expression inthe overexpressing clones. Moreover, transient transfection with siRNA silencing P21CIP1, but not the controlsiRNA, resulted in a reduction in monocytic differentiation, accompanied by an increase in proliferation. Inconclusion, our work demonstrates that gelsolin, by itself, is capable of inducing monocytic differentiation inU937 leukaemia cells, most probably through p21CIP1 activation.