Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells

Abstract

Interferon (IFN-␣) is effective therapy for polycythemia vera (PV) patients, but it is

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Because type I interferons (IFN) target JAK2 V617F + progenitors in PV through activation of MAPK and STAT1, thereby increasing TP53 transcription, the combination of IFN with MDM2 inhibitors, which prevent the degradation of TP53, provides an opportunity to induce TP53-dependent apoptosis [170]. Indeed, combination treatment with IFN and the MDM2 antagonist Nutlin-3 triggered apoptosis in PV CD34 + cells and inhibited proliferation of these cells to a greater extent than normal CD34 + cells [170]. The combination also reduced the proportion of JAK2 V617F progenitors in PV patients.…”

“…The combination also reduced the proportion of JAK2 V617F progenitors in PV patients. Combination treatment of PV and primary MF CD34 + cells, followed by transplantation into immunodeficient mice, decreased the extent of donor-derived chimerism as well as the JAK2 V617F allele burden, suggesting that such combinatorial approaches may deplete MPN hematopoietic stem cells [170]. The clinical candidate MDM2 antagonist Idasanutlin is currently in a phase I trial in patients with PV or ET, with a provision for adding pegylated IFN in subjects without or with partial remission after three cycles of therapy.…”

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

“…Nakatake and coworkers demonstrated in human cell lines that JAK2V617F alters p53 responses to DNA damage through upregulation of La antigen, which increases MDM2 protein translation. 24 We have recently reported that MDM2 levels are increased in primary PV CD34 1 cells, 13 whereas the p53 levels are reduced in CD34 1 cells from both patients with PV and PMF. The cis-imidazoline compounds termed nutlins were the first potent and selective MDM2 inhibitors, and their discovery stimulated widespread interest in the design of small molecule p53-MDM2 inhibitors.…”

“…Our laboratory has attempted to target the p53 pathway with pharmacologic agents with the hope of reducing or eliminating the numbers of MPN stem cells. 13 Because MPNs are likely the result of multiple genetic mutations as well as epigenetic events that are difficult to recapitulate in rodent models, we have used primary cells from MPN patients to evaluate these potential therapeutic agents. 13,14 The tumor suppressor p53 plays an important role in the control of DNA repair, the cell cycle, apoptosis, and cancer surveillance.…”

“…13 Because MPNs are likely the result of multiple genetic mutations as well as epigenetic events that are difficult to recapitulate in rodent models, we have used primary cells from MPN patients to evaluate these potential therapeutic agents. 13,14 The tumor suppressor p53 plays an important role in the control of DNA repair, the cell cycle, apoptosis, and cancer surveillance. 15,16 Most MPN patients have wild-type (WT) p53, whereas p53 mutations and heterozygous deletions have been almost exclusively identified in MPN patients who are undergoing transformation to acute leukemia.…”