Kras promotes myeloid differentiation through Wnt/β-catenin signaling

Wild-type Kras, a small GTPase, inactivates Ras growth-promoting signaling. However, the role of Kras in differentiation of myeloid cells remains unclear. This study showed the involvement of Kras in a novel regulatory mechanism underlying the dimethyl sulfoxide (DMSO)-induced differentiation of human acute myeloid leukemia HL-60 cells. Kras was found to positively regulate DMSO-induced differentiation, with the activity of Kras increasing upon DMSO. Inhibition of Kras attenuated CD11b expression in differentiated HL-60 cells. GSK3 beta, an important component of Wnt signaling, was found to be a downstream signal of Kras. Phosphorylation of GSK3 beta was markedly enhanced by DMSO treatment. Moreover, inhibition of GSK3 beta enhanced CD11b expression and triggered the accumulation in the nucleus of beta-catenin and Tcf in response to DMSO. Inhibitors of beta-catenin-mediated pathways blocked CD11b expression, further indicating that beta-catenin is involved in the differentiation of HL-60 cells. Elevated expression of C/EBPa and C/EBP. accompanied by the expression of granulocyte colony-stimulating factor (G-CSF) receptor was observed during differentiation. Taken together, these findings suggest that Kras engages in cross talk with the Wnt/beta-catenin pathway upon DMSO treatment of HL-60 cells, thereby regulating the granulocytic differentiation of HL-60 cells. These results indicate that Kras acts as a tumor suppressor during the differentiation of myeloid cells.