Fig. 6

Pml regulates LICs non-cell autonomously through Il6 and Cxcl1 pathways. a The schematic overview of the experimental design is depicted in the upper panel. The numbers of leukemic cells with different genotype, derived from co-cultures treated with the combination of anti-IL6R and anti-CXCR2, are shown in the lower panel. Data are shown as average ± SEM. (n ≥ 2 independent experiments). b Co-cultures of MSCs Pml ^+/+ and HoxA9–Meis1⁺GFP⁺ leukemic cells were untreated (NT) as control, or treated with anti-CXCR2 in combination of anti-IL6R. Co-cultures with MSCs Pml ^−/− and HoxA9–Meis1⁺GFP⁺ leukemic cells were untreated as control, or treated with recombinant Il6 and Cxcl1 proteins. Leukemic cells were then re-plated onto new MSCs (Pml ^+/+ or Pml ^−/−); secondary co-cultures were analyzed for the presence of GFP⁺ckit⁺ cells. The relative numbers of GFP⁺ckit⁺ cells in the different conditions are shown. Data are shown as average ± SEM. c Schematic representation of the proposed model. In MSCs, Pml regulates the secretion of pro-inflammatory soluble factors, which sustain the maintenance of leukemic cells and those enriched for LIC capacity. Pml sustains leukemic cells in a non-cell-autonomous manner, in cooperation with the cell-autonomous mechanisms within LICs, as previously described. d Pml degradation, (achieved for example through treatment with arsenic trioxide (AS₂O₃)), contributes to eliminate leukemic cells