Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells

Abstract

Current therapy for myelofibrosis (MF) results in a limited prolongation of patient survival. In order to improve treatment outcomes, we developed a strategy to effectively deplete MF hematopoietic stem/progenitor cells (HSPCs). In the present study, an imipridone, ONC201, was combined with RG7112, an antagonist of MDM2, a p53 negative regulator, to activate downstream events of the p53 and TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR) pathways. As compared to treatment with the individual drugs, the combination of ONC201 and RG7112 promoted greater degrees of apoptosis of MF CD34+ cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F+ and calreticulin mutated colonies assayed from MF CD34+ cells, but allowed for the persistence or appearance of JAK2 wild type colonies. Treatment with ONC201 combined with RG7112 could be a potentially effective strategy for treating MF patients.

Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients

“…We have previously shown the potential of targeting TP53 and MYC to extinguish the leukaemic clone in a novel drug combination in other MPNs [ 10 , 11 ]. Also, a recent study proposed that targeting TP53 in combination with the TNF-related apoptosis inducing pathway could potentially be an effective strategy for treating MF patients [ 12 ]. Furthermore, SSRP1 a subunit of the FACT complex, was identified as one of the top 20 hits from an shRNA screen to identify critical genes in myelofibrosis [ 13 ] and since NF-ĸB has been reported to be activated in MF [ 14 , 15 ] we hypothesised that CBL0137 may have utility in the treatment of MF.…”