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Area of Science:

  • * Molecular Biology
  • * Pharmacology
  • * Oncology

Background:

  • * The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is crucial for regulating hematopoiesis, immunity, and inflammation.
  • * Aberrant JAK/STAT signaling is implicated in various malignancies, notably myeloproliferative neoplasms (MPNs).
  • * Current JAK inhibitors like ruxolitinib are effective but costly, necessitating low-cost alternatives.

Purpose of the Study:

  • * To identify small molecules that modulate JAK/STAT signaling using a low-complexity model system.
  • * To evaluate the efficacy of identified compounds, particularly methotrexate, in suppressing JAK/STAT activation in human cells and MPN models.
  • * To explore the potential of low-dose methotrexate as a therapeutic agent for inflammatory diseases and JAK/STAT-associated hematological malignancies.

Main Methods:

  • * Utilized the Drosophila melanogaster JAK/STAT pathway for high-throughput screening of small molecules.
  • * Assessed the impact of methotrexate on human JAK/STAT signaling and STAT5 phosphorylation in JAK2 V617F-mutated cells.
  • * Investigated the mechanism of action, including independence from dihydrofolate reductase (DHFR).

Main Results:

  • * Methotrexate and aminopterin were identified as potent suppressors of STAT activation.
  • * Methotrexate effectively inhibited human JAK/STAT signaling and STAT5 phosphorylation in MPN cells, independent of DHFR.
  • * Methotrexate demonstrated comparable efficacy to ruxolitinib but preserved cellular response to erythropoietin.

Conclusions:

  • * Methotrexate and aminopterin represent novel, low-cost modulators of the JAK/STAT pathway.
  • * Low-dose methotrexate's anti-inflammatory and immunosuppressive effects are likely mediated by JAK/STAT pathway suppression.
  • * Findings suggest potential therapeutic benefits of low-dose methotrexate for patients with MPNs and inflammatory conditions, offering a cost-effective alternative to existing treatments.