Overexpression of c-Myc and inactivation of p53 are hallmarks of human Burkitt's lymphomas. We had previously showed that transduction of murine p53-null bone marrow cells with a Myc-encoding retrovirus is sufficient for B lymphomagenesis. To address the role of Myc in tumor sustenance, we generated lymphomas induced by the Mycestrogen receptor fusion protein (MycER). Engrafted hosts were continuously treated with the ER ligand 4-hydroxytamoxifen (4-OHT) to allow tumor formation. Subsequent inactivation of MycER via 4-OHT deprivation resulted in tumor stasis but only partial regression. At the cellular level, dormant neoplastic lymphocytes withdrew from mitosis and underwent further B-cell differentiation. Concomitantly, they up-regulated genes involved in lymphocyte proliferation and survival, most notably interleukin 10 receptor A (IL10Ra) and CD20, the target for antibody therapy with Rituxan. We found that overexpression of IL10RA affords significant proliferative advantages and in 4-OHT-deprived animals correlates with eventual tumor relapse. Both dormant and relapsing tumors maintain IL10RA expression suggesting that they might be sensitive to emerging drugs targeting the IL-10 pathway. Upregulation of CD20 following Myc inactivation was also observed in immortalized human lymphocytes. Importantly, in this system, Myc OFF CD20 HIGH cells were more prone to Rituxan-induced apoptosis than Myc ON CD20 MED . Thus, targeting Myc, while moderately effective on its own, shapes the phenotype of dormant neoplastic cells and sensitizes them to adjuvant molecular therapies. (Cancer Res 2005; 65(12): 5454-61)