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

Min Lu,Douglas Tremblay,Lijuan Xia,Nada Elmansy,Ronald Hoffman,Cara Clementelli

doi:10.1038/s41375-021-01446-4

Min Lu, Douglas Tremblay + Show 4 more

Open Access

https://doi.org/10.1038/s41375-021-01446-4

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Journal: Leukemia	Publication Date: Oct 12, 2021
Citations: 2	License type: open-access

Affiliation: Tisch Hospital, Icahn School of Medicine at Mount Sinai

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.

Highlights

Myelofibrosis (MF), a myeloproliferative neoplasm (MPN), arises at the level of hematopoietic stem progenitor cells (HSPCs) due to a series of mutational events that result in activation of JAK/STAT signaling [1, 2]
The data showed that the percentage of TNF-related apoptosis-inducing ligand (TRAIL)+, DR4+ or DR5+ cells was significantly decreased in MF CD34+ cells as compared to Normal donor (ND) CD34+ cells
It is anticipated that a successful strategy for treating MF that would culminate in a substantial improvement in overall MF patient survival would require depletion or elimination of malignant HSPCs, the emergence of normal hematopoiesis and be associated with modest hematological and non-hematological toxicity

Summary

Introduction

Myelofibrosis (MF), a myeloproliferative neoplasm (MPN), arises at the level of hematopoietic stem progenitor cells (HSPCs) due to a series of mutational events that result in activation of JAK/STAT signaling [1, 2]. JAK2 inhibitor therapy for patients with advanced forms of MF results in a reduction in the degree of splenomegaly and improvement in the systemic symptoms but does not prevent disease progression and only modestly prolongs overall survival [11,12,13,14]. We have reported a phase 1 trial of the oral nutlin, RG7388 (idasanutlin), in polycythemia vera (PV) patients intolerant or refractory to hydroxyurea or interferon therapy, which resulted in hematological responses, reduction in the degree of splenomegaly, an improvement in symptoms and a reduction in the JAK2V617F variant allele frequency (VAF) [20]. Additional trials of MDM2 antagonists in MF patients have led to reductions in spleen size, improvement of systemic symptoms, and reduction in the VAF of MPN driver mutations (NCT04097821, NCT04485260, NCT04640532). The appearance of these TP53 mutations diminished with discontinuation of nutlin therapy and was not associated with drug resistance or progression to MF or MPN-blast phase (BP) [23]

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Conclusion