Current Outlook on Molecular Pathogenesis and Treatment of Myeloproliferative Neoplasms

Abstract

Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.

Carbazole Derivatives as STAT Inhibitors: An Overview

“…Associated with STATs is the Janus kinases (JAK), belonging to the tyrosine kinases family, responsible for activating the STAT cascade that initiates, ultimately, gene transcription. [127] Literature data report that carbazoles (Table 1) could act by downregulating STAT proteins (particularly STAT-3), and also affecting interleukins and i-NOS production. [126] According to some studies their effects could be due to the involvement of the JAK/STAT pathway.…”

Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies

“…On the basis of a deeper understanding of the molecular events involved in tumorigenesis and proliferation, a number of kinase-mediated signaling pathways, such as the Aurora kinases, VEGF/PDGF, and the Src families of tyrosine kinases, have been identified as potential therapeutic targets for the treatment of hematologic malignancies and solid tumors (4,5). Ilorasertib is a novel ATP-competitive multitargeted kinase inhibitor of Aurora kinases (A, B, C), as well as all known members of the VEGF/PDGF and Src families of tyrosine kinases (20).…”

“…Thus, there remains an unmet need to identify new agents and therapeutic approaches to improve clinical outcomes in patients with these difficult-to-treat diseases. Because oncogenic mutations in kinases are implicated in numerous cancer types, targeting of the kinase-mediated signaling pathways is a well-recognized approach to developing cancer therapies (4,5). …”

Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

“…MF can be primary (PMF) or secondary to the MPNs polycythemia vera (PV) or essential thrombocythemia (ET) (post-PV or post-ET, respectively) [2]. MF is characterized by stem cell–derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, cytopenias, extramedullary hematopoiesis (eg, splenomegaly), cachexia, and constitutional symptoms including night sweats, fevers, weight loss, and fatigue [3-5]. Disease complications also include infections, portal hypertension, bleeding, extremity pain, and progression of disease with blastic transformation, resembling acute leukemia [5-8].…”