SPARC-deficient mice are less sensitive to serial 5-FU injections due to the absence of SPARC expression by niche cells. (A) SPARC mRNA expression by cell type of the adult BM niche including mature osteoblasts (mOBs), osteoprogenitors (iOBs), and the fraction containing mesenchymal stem cells (MSCs) and endothelial cells (ECs) (N = 10 per group; mean and SD). (B) SPARC-deficient mice show enhanced survival when injected with 5-FU at a dose of 150 μg/g at 10-day intervals (N = 10-11 per group; median survival: WT = 43 days, Sparc^−/− = 71 days; ****P < .001; log-rank [Mantel-Cox] test and Gehan-Breslow-Wilcoxon test). Time points of 5-FU injections are indicated with arrows. (C) Straight chimeras that lack SPARC expression by hematopoietic cells have no survival benefit in the serial 5-FU experiment. C57Bl/6J mice were transplanted with WT (littermate control) or Sparc^−/− BM, and 5-FU treatment (120 μg/g at 10-day intervals) was started 12 weeks after transplantation (N = 9; median survival: WT = 23 days, Sparc^−/− = 20 days; no significant difference). (D) Lack of SPARC expression by non-hematopoietic cells is sufficient to provide a survival benefit in the serial 5-FU experiment. WT or Sparc^−/− mice were transplanted with WT BM (CD45.1/2), and 5-FU treatment (120 μg/g at 10-day intervals) was started 12 weeks after transplantation. (N = 13-17; median survival: WT = 42 days, Sparc^−/− = 169; ****P < .001; log-rank [Mantel-Cox] test and Gehan-Breslow-Wilcoxon test).