The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells.

Abstract

The Philadelphia chromosomal-negative chronic myeloproliferative neoplasms (MPNs) originate at the level of the hematopoietic stem cell (HSC). The protracted clinical course of the MPNs has limited the use of potentially toxic treatment modalities, which may eliminate the responsible malignant clone. Treatment with low doses of RG7112, an orally available small-molecule inhibitor of p53-MDM2, both alone and combined with pegylated interferon α 2a (Peg-IFNα 2a), significantly decreased MPN colony-forming unit-granulocyte macrophage and burst-forming unit-erythroid numbers and preferentially eliminated the total number of JAKV617F(+) MPN hematopoietic progenitor cells. The effects of RG7112 and Peg-IFNα 2a on MPN progenitor cells were dependent on blocking p53-MDM2 interactions and activating the p53 pathway, thereby increasing MPN CD34(+) cell apoptosis. Treatment of polycythemia vera (PV) and primary myelofibrosis (PMF) CD34(+) cells with low doses of RG7112 and Peg-IFNα 2a before their transplantation into immune-deficient mice decreased the degree of donor-derived chimerism as well as the JAK2V617F allele burden, indicating that these drugs can each alone or in combination deplete MPN HSCs. These results provide a rationale for the use of combinations of low doses of RG7112 and Peg-IFNα 2a for the treatment of PV or PMF patients with the intent of altering their natural history.

• Authors: Min Lu, Lijuan Xia, Yan Li, Xiaoli Wang, Ronald Hoffman
• Journal: Blood (Blood) Vol. 124 Issue 5 Pg. 771-9 (Jul 31 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24869939 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Antiviral Agents
• Imidazolines
• Interferon-alpha
• RG7112
• Recombinant Proteins
• Polyethylene Glycols
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• JAK2 protein, human
• Janus Kinase 2
• peginterferon alfa-2a

Topics

• Administration, Oral
• Amino Acid Substitution
• Animals
• Antiviral Agents (pharmacology)
• Female
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells (metabolism, pathology)
• Heterografts
• Humans
• Imidazolines (pharmacology)
• Interferon-alpha (pharmacology)
• Janus Kinase 2 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation, Missense
• Polycythemia Vera (drug therapy, genetics, metabolism, pathology)
• Polyethylene Glycols (pharmacology)
• Primary Myelofibrosis (drug therapy, genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (pharmacology)