.In tumor dormancy, tumor cells perist in the host for a long time but do not grow. In the BCR/ABL DA1-3b mouse model of acute myeloid leukemia, dormant tumor cells may persist in the host in a state of equilibrium with the CD8+ CTL-mediated immune response, by actively inhibiting T-cells. Dormant tumor cells also show a progressive decrease of SOCS1 gene expression and a deregulation of the JAK/STAT pathway, due to methylation of SOCS1 gene promoter. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs but resistance decreased when SOCS1 expression was restored by demethylation or gene transfer. AG490 JAK2 inhibitor decreased the resistance of dormant tumor cells to CTLs, but MG132 proteasome inhibitor was effective only in SOCS1-transfected cells. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing. Resistance of dormant tumor cells to apoptosis was also observed when induced by irradiation, cytarabine, or imatinib mesylate, but was reduced by SOCS1 gene transfer. Thus, tumor cells that remain dormant for long periods in the host in spite of a specific CTL immune response may deregulate their JAK/STAT pathways and develop cross-resistance to various treatments. These data suggest new possible therapeutic targets to eradicate dormant tumor cells.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]