MONOCYTIC DIFFERENTIATION AND SYNTHESIS OF PROTEINS ASSOCIATED WITH APOPTOSIS IN HUMAN LEUKEMIA U-937 CELLS ACQUIRING RESISTANCE TO VINCRISTINE

Human leukemia U-937/WT cells were exposed to stepwise increased conce ntrations of Vincristine so that Vincristine-resistant cell sublines ( termed U-937/RV) were developed. Established U-937/RV cell sublines ha ve continuously propagated over a year, both in absence and presence o f VCR, and have demonstrated similar features. In contrast to U-937/WT cells, U-937/RV cells have longer doubling time, and are more differe ntiated as determined by appearance of distinct morphological features and synthesis of mRNA that codes for the monocyte colony-stimulating factor-1 receptor (c-fms). Both apoptosis-suppressing Bcl-2 and Bcl-X( L) proteins were undectable in U-937/WT cells, whereas Bcl-2 was nearl y detectable and Bcl-X(L) readily detectable in U-937/RV cells. The ap optosis-promoting Bar protein was also absent in U-937/WT cells and re adily detected in U-937/RV cells. Vincristine-resistant cells with dif ferent levels of resistance synthesize similar levels of c-fms mRNA an d Bar protein. Finally, unlike U-937/WT cells, U-937/RV cells have no ability to induce tumors when xenografted in immunodeficient mice. The findings collectively suggest that development of resistance to Vincr istine in U-937/WT cells may correlate with cell differentiation and s ynthesis of proteins that regulate apoptosis.