Polycythemia vera: the current status of preclinical models and therapeutic targets

ABSTRACT

Introduction

Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN). PV is characterized by erythrocytosis, leukocytosis, thrombocytosis, increased hematocrit, and hemoglobin in the peripheral blood. Splenomegaly and myelofibrosis often occur in PV patients. Almost all PV patients harbor a mutation in the JAK2 gene, mainly represented by the JAK2^V617F point mutation.

Areas covered

This article examines the recent in vitro and in vivo available models of PV and moreover, it offers insights on emerging biomarkers and therapeutic targets. The evidence from mouse models, resembling a PV-like phenotype generated by different technical approaches, is discussed. The authors searched PubMed, books, and clinicaltrials.gov for original and review articles and drugs development status including the terms Myeloproliferative Neoplasms, Polycythemia Vera, erythrocytosis, hematocrit, splenomegaly, bone marrow fibrosis, JAK2^V617F, Hematopoietic Stem Cells, MPN cytoreductive therapy, JAK2 inhibitor, histone deacetylase inhibitor, PV-like phenotype, JAK2^V617F BMT, transgenic JAK2^V617F mouse, JAK2 physiologic promoter.

Expert opinion

Preclinical models of PV are valuable tools for enabling an understanding of the pathophysiology and the molecular mechanisms of the disease. These models provide new biological insights on the contribution of concomitant mutations and the efficacy of novel drugs in a ‘more faithful’ setting. This may facilitate an enhanced understanding of pathogenetic mechanisms and targeted therapy.

KEYWORDS:

• Myeloproliferative neoplasms
• polycythemia vera
• JAK2^V617F
• MPN mouse model

Article highlights

• Polycythemia vera is characterized by the presence of a V617F point mutation or exon 12 mutations in JAK2 gene.

• The hematopoietic stem cells of Polycythemia vera are clonal; the JAK2^V617F driver mutation is found in long-term hematopoietic stem cells.

• The bone marrow transplantation of JAK2^V617F mutated cells is sufficient to induce a Polycythemia vera–like phenotype in mice.

• The transgenic mouse models focused the attention on the expression level of the mutation as phenotype modulator.

• The transgene integration site in the host genome and the time of activation and expression are of key importance to model the disease phenotype, as highlighted by knock-in mouse models.

• Beside the JAK2^V617F, additional mutations worsen the prognosis for polycythemia vera patients in terms of overall, leukemia-free and progression-free survival.

• Dual-specificity phosphatase (DUSP1) and the phosphatidylnositol 3-Kinase (PI3K) pathway are potential therapeutic targets worthy of further investigation.

This box summarizes key points contained in the article.

Declaration of interest

AM Vannucchi is an Advisory Board member at Novartis, Celgene, Incyte, Italfarmaco, and AbbVie and has received lecturing fees from Novartis, Celgene and CTI. P Guglielmelli has received lecturing fees from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is on the Advisory Board of Novartis who developed the drug Midostaurin.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was supported by AIRC 5 per mille Grant #21267 project Mynerva and supported by Progetto finalizzata Ministero Salute RF––2016-02362930.