Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for acute myeloblastic leukemia (AML) cells. Murine double minute 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), can function both to induce cell proliferation and enhance cell survival, and is frequently overexpressed in leukemias. Therefore, we focused on the importance of MDM2 protein in GM-CSF–dependent versus GM-CSF– independent growth of AML cells. The TF-1 AML cell line, which has both wtp53 and mutant p53 genes, showed GM-CSF–dependent growth; deprivation of GM-CSF resulted in G1 growth arrest and apoptosis. MDM2 mRNA and protein were highly expressed in proliferating TF-1 cells in the presence of GM-CSF and decreased significantly with deprivation of GM-CSF. In contrast, p53 protein increased with GM-CSF deprivation. Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-CSF deprivation, and is associated with decreased p53 protein expression. Moreover, a variant of TF-1 cells that grows in a GM-CSF–independent fashion also expressed high levels of MDM2 and low levels of p53. These results suggest that GM-CSF–independent growth of AML cells is associated with overexpression of MDM2 protein and related modulation of p53 expression. © 1998 by The American Society of Hematology.
Ex vivo expansion of hematopoietic progenitor cells in the umbilical cord blood mononuclear cells (CB‐MNC) was investigated in liquid culture system with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]‐3, IL‐6, granulocyte‐colony stimulating factor [G‐CSF], erythropoietin [EPO], and interferon [INF]‐γ). Non‐lineage‐committed hematopoietic progenitor cells and lineage committed hematopoietic progenitor cells were represented as CD34+CD38− and CD34+CD38+ subpopulations, respectively. Although absolute CD34+CD38− cell numbers decreased even in the presence of multicytokines, the combinations of SCF plus IL‐6 and SCF plus IL‐3 plus IL‐6 plus INF‐γ were significantly effective in maintaining CD34+CD38− cells than the other combinations (P < 0.05). After 4 weeks of culture, CD34+CD38− cells disappeared in all combinations of cytokines. Absolute CD34+CD38+ cell numbers increased in the presence of cytokines. Maximal expansion of CD34+CD38+ cells were observed in the combinations of SCF plus IL‐3 plus IL‐6 plus EPO (19.8 ± 3.3 ‐fold) and SCF plus IL‐3 plus IL‐6 plus G‐CSF (18.3 ± 2.6). The combination of SCF plus IL‐3 plus IL‐6 was also effective to expand CD34+CD38+ cells (15.8 ± 3.9). However, the expansion was transient and they decreased to zero within 3 weeks. In the combinations of SCF plus IL‐6 and SCF plus IL‐3 plus IL‐6 plus INF‐γ, maximal expansion was inferior to the others but CD34+CD38+ cells were maintained more than 4 weeks. These results suggested that the indication of CBT can be expanded into older children by ex vivo augmentation of CB hematopoietic progenitor cells using multi‐cytokines.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for acute myeloblastic leukemia (AML) cells. Murine double minute 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), can function both to induce cell proliferation and enhance cell survival, and is frequently overexpressed in leukemias. Therefore, we focused on the importance of MDM2 protein in GM-CSF–dependent versus GM-CSF– independent growth of AML cells. The TF-1 AML cell line, which has both wtp53 and mutant p53 genes, showed GM-CSF–dependent growth; deprivation of GM-CSF resulted in G1 growth arrest and apoptosis. MDM2 mRNA and protein were highly expressed in proliferating TF-1 cells in the presence of GM-CSF and decreased significantly with deprivation of GM-CSF. In contrast, p53 protein increased with GM-CSF deprivation. Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-CSF deprivation, and is associated with decreased p53 protein expression. Moreover, a variant of TF-1 cells that grows in a GM-CSF–independent fashion also expressed high levels of MDM2 and low levels of p53. These results suggest that GM-CSF–independent growth of AML cells is associated with overexpression of MDM2 protein and related modulation of p53 expression. © 1998 by The American Society of Hematology.
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