Inactivation of Myc in murine two-hit B lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20: implications for adjuvant therapies.
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 Myc-estrogen 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 alpha (IL10Ralpha) and CD20, the target for antibody therapy with Rituxan. We found that overexpression of IL10Ralpha affords significant proliferative advantages and in 4-OHT-deprived animals correlates with eventual tumor relapse. Both dormant and relapsing tumors maintain IL10Ralpha expression suggesting that they might be sensitive to emerging drugs targeting the IL-10 pathway. Up-regulation 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.
Yu
Duonan
D
Department of Pathobiology and Biomedical Informatics Core, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6051, USA.
Dews
Michael
M
Park
Andrea
A
Tobias
John W
JW
Thomas-Tikhonenko
Andrei
A
D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016259:Genes, myc / Q000235:genetics*; D016753:Interleukin-10 / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000069283:Rituximab; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018123:Receptors, Interleukin; D013629:Tamoxifen; D016753:Interleukin-10; C016601:afimoxifene; D000069283:Rituximab