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Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells.
- Source :
-
Leukemia [Leukemia] 2022 Mar; Vol. 36 (3), pp. 733-745. Date of Electronic Publication: 2021 Oct 12. - Publication Year :
- 2022
-
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 <superscript>+</superscript> cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F <superscript>+</superscript> and calreticulin mutated colonies assayed from MF CD34 <superscript>+</superscript> 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.<br /> (© 2021. The Author(s).)
- Subjects :
- Cells, Cultured
Drug Delivery Systems
Hematopoietic Stem Cells metabolism
Humans
Primary Myelofibrosis metabolism
Signal Transduction drug effects
Antineoplastic Agents pharmacology
Hematopoietic Stem Cells drug effects
Imidazoles pharmacology
Imidazolines pharmacology
Primary Myelofibrosis drug therapy
Pyridines pharmacology
Pyrimidines pharmacology
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 36
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 34642468
- Full Text :
- https://doi.org/10.1038/s41375-021-01446-4