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Abstract: The Notch1 signaling pathway plays an essential role in cell growth and differentiation. Over-expression of the intracellular Notch1 domain (ICN1) in murine hematopoietic cells is able to induce robust T-cell acute lymphoblastic leukemia (T-ALL) in mice. Here we explored the drug sensitivity of T-ALL cells in two subpopulations of CD8+CD4+ and CD8+CD4− cells in Notch1-induced T-ALL mice. We found that Notch1 induced T-ALL cells could be decreased by chemotherapeutic drug cyclophosphamide (CTX). CD8+CD4− T-ALL cells were more sensitive to CTX treatment than CD8+CD4+ T-ALL cells. The percentage of apoptotic cells induced by CTX treatment was higher in CD8+CD4− T-ALL cells. T-ALL cells were also inhibited by inhibitor of mTORC1 rapamycin. CD8+CD4+ T-ALL cells were more susceptible to rapamycin treatment than CD8+CD4− T-ALL cells. Rapamycin treatment selectively arrested more CD8+CD4+ T-ALL cells at G0 phase of cell cycle. A combination of the two drugs significantly improved overall survival of T-ALL bearing mice when compared with CTX or rapamycin alone. These results indicated that CD8+CD4+ and CD8+CD4− leukemia cell populations had distinct drug sensitivity. [Copyright &y& Elsevier]