Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma

Normal hematopoiesis is suppressed during the development of leukemia. In the T-ALL leukemia mouse model described in our recent study (Hu X, et al. Blood 2009), the impacts of leukemic environment on normal hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were distinct, in that normal HSCs were preserved in part because of increased mitotic quiescence of HSCs and resulting exhaustion of HPCs proliferation. Stem cell factor (SCF) secreted by leukemic cells in Nalm6 B-ALL model was previously suggested to force normal HSCs/HPCs out of their bone marrow niches and allow leukemic cells to occupy the niches (Colmone A, et al. Science 2008). Here we found that stem cell factor (SCF) expression in PB and BM of T-ALL model was increased, but SCF mRNA and protein levels in normal hematopoietic cells were higher than those in leukemia cells, which suggested that upregulated SCF was mainly contributed by non-leukemic cells in response to the leukemia development. To further elucidate the molecular mechanisms, microarray analysis was conducted on normal HSCs in this model and verified by real-time RT-PCR. The expression of Hes1 and its downstream target p21 were elevated in normal HSCs, whereas their expression showed no significant alteration in HPCs. Interestingly, although overexpression of Hes1 by retroviral infection inhibited the in vitro colony formation of normal hematopoietic cells, in vivo results demonstrated that normal Lin^- cells and HSPCs were better preserved when normal Lin^- cells with Hes1 overexpression were co-transplanted with T-ALL leukemia cells. Our results suggested that the differential expression of Hes1 between HSCs and HPCs resulted in the distinct responses of these cells to the leukemic condition, and that overexpression of Hes1 could enhance normal HSPCs in the leukemic environment.