nutlin-3a and Polycythemia-Vera

Interferon (IFN-α) is effective therapy for polycythemia vera (PV) patients, but it is frequently interrupted because of adverse events. To permit the long-term use of IFN, we propose combining low doses of IFN with Nutlin-3, an antagonist of MDM2, which is also capable of promoting PV CD34(+) cell apoptosis. Combination treatment with subtherapeutic doses of Peg IFN-α 2a and Nutlin-3 inhibited PV CD34(+) cell proliferation by 50% while inhibiting normal CD34(+) cells by 30%. Combination treatment with Nutlin-3 and Peg IFN-α 2a inhibited PV colony formation by 55%-90% while inhibiting normal colony formation by 22%-30%. The combination of these agents also decreased the proportion of JAK2V617F-positive hematopoietic progenitor cells in 6 PV patients studied. Treatment with low doses of Peg IFN-α 2a combined with Nutlin-3 increased phospho-p53 and p21 protein levels in PV CD34(+) cells and increased the degree of apoptosis. These 2 reagents affect the tumor suppressor p53 through different pathways with Peg IFN-α 2a activating p38 MAP kinase and STAT1, leading to increased p53 transcription, whereas Nutlin-3 prevents the degradation of p53. These data suggest that treatment with low doses of both Nutlin-3 combined with Peg IFN-α 2a can target PV hematopoietic progenitor cells, eliminating the numbers of malignant hematopoietic progenitor cells.

Topics: Apoptosis; Blotting, Western; Drug Therapy, Combination; Hematopoietic Stem Cells; Humans; Imidazoles; In Vitro Techniques; Interferon-alpha; Janus Kinase 2; Mutation; Piperazines; Polycythemia Vera; Polyethylene Glycols; Polymerase Chain Reaction; Proto-Oncogene Proteins c-mdm2; Recombinant Proteins; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Topics: Apoptosis; Drug Therapy, Combination; Hematopoietic Stem Cells; Humans; Imidazoles; Interferon-alpha; Piperazines; Polycythemia Vera; Polyethylene Glycols; Proto-Oncogene Proteins c-mdm2; Recombinant Proteins; Tumor Suppressor Protein p53