We are interested in genetic programs and mutations which impact on tumor development and sensitivity to anticancer therapies. Utilizing Emu-myc transgenic mice, which spontaneously develop aggressive B-cell lymphomas, we aimed here to study the effects of drug responses in vivo. For that purpose, primary lymphomas from the Emu-myc transgenic mice were transplanted in several immunocompetent recipients and exposed to a single dose Cyclophosphamide (CTX), a standard component of chemotherapeutic regimens used to treat human B-cell lymphomas. Approximately one half of recipient mice are cured with this treatment (Never Relapse Lymphomas, NR), while in other half lymphomas relapse over time (Relapse Prone Lymphomas, RP), allowing us to treat these relapsed mice with progressively shorter durations of remission into full-blown clinical resistance (Resistant Lymphomas, RES). Looking at the differences between NR, RP and RES lymphomas, each in therapy-naive state or after drug challenge, we aimed here to decipher the genetic and biochemical components determining the susceptibility of lymphoma cells to respond to standard chemotherapeutic drugs. Overall design: Immunocompetent recipient mice, transplanted with an aliquot of primary lymphoma cells explated from transgenic Emu-myc mice, were exposed to a single dose of Cyclophosphamide (CTX), a standard component of chemotherapeutic regimens used to treat human B-cell lymphomas. After obtaining long-term therapy response data in mice, the global expression profiles were obtained from aliquots of these same lymphomas in therapy-naive state, after acute in vivo drug challenge (where lymphomas engrafted in recipient mice were explated 4h after applying single dose CTX treatment) or long-term responses (where the engrafted lymphomas relapsed over time after CTX treatment and were explated from recipient mice). Ultimate therapy resistance mechanisms were analyzed in samples of relapsed lymphomas above, which were submitted to another two rounds of transplantation into new hosts, CTX treatment and relapse.