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The impact of JAK/STAT inhibitor ruxolitinib on the genesis of lymphoproliferative diseases

ABSTRACT: Background/aim:Ruxolitinib, a JAK/STAT signaling pathway inhibitor targeted drug, has been approved for the controlling of disease symptoms and splenomegaly in patients with myeloproliferative neoplastic diseases. Recently, it has been proposed that ruxolitinib-induced JAK/STAT pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. However, the biological basis and significance of this pharmacobiological adverse event is unknown. The aim of this bioinformatics study is to detect any possible confounding effects of ruxolitinib on the genesis of lymphoproliferative disorders. Materials and methods:The gene expression data were retrieved from the E-MTAB-783 Cancer Genome Project database. Gene expression data for all available genes in 26 cell lines belonging to various types of lymphomas were chosen for use in this in silico analysis. Results:We identified genes that were significant in developing resistance to ruxolitinib in lymphoma cell lines. Conclusion:Based on the results of our present study, ruxolitinib may potentially lead to the pathological expression of the transcription factors important in lymphoma genesis, neoplastic commitment on the progenitor lymphoid cells, inhibition of repressor transcriptions protective for lymphoma development, inhibition of apoptosis, promotion of neoplastic proliferation, transcriptional activation, and proliferation of malignant neoplastic B cells.

SUBMITTER: Turk C

PROVIDER: S-EPMC7018380 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The impact of JAK/STAT inhibitor ruxolitinib on the genesis of lymphoproliferative diseases

Türk Can C Okay Müfide M Türk Seyhan S Temirci Elif Sena ES Javad Osama O Aksu Salih S Sayınalp Nilgün N Haznedaroğlu İbrahim Celalettin İC

Turkish journal of medical sciences 20190418 2

<h4>Background/aim</h4>Ruxolitinib, a JAK/STAT signaling pathway inhibitor targeted drug, has been approved for the controlling of disease symptoms and splenomegaly in patients with myeloproliferative neoplastic diseases. Recently, it has been proposed that ruxolitinib-induced JAK/STAT pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. However, the biological basis and significance of this pharmacobi ...[more]

PMID: 30997981

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Project description:BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & findingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

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The impact of JAK/STAT inhibitor ruxolitinib on the genesis of lymphoproliferative diseases

Publications

The impact of JAK/STAT inhibitor ruxolitinib on the genesis of lymphoproliferative diseases

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