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Regulation of STAT5 phosphorylation and interaction with SHP1 by lnc-AC004893, a long non-coding RNA overexpressed in

Junjun Yang1, Jichen Ruan2, Bin Zhou3

  • 1Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.

Hematology (Amsterdam, Netherlands)
|July 16, 2024
PubMed
Abstract

Insights

This study reveals that the long noncoding RNA lnc-AC004893 is upregulated in myeloproliferative neoplasms (MPNs) and promotes disease progression by regulating the JAK2/STAT5 pathway. Inhibiting lnc-AC004893 suppressed MPN cell growth and improved survival in a mouse model, suggesting it as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Constitutive activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway is a key driver in myeloproliferative neoplasms (MPNs).
  • The role of long noncoding RNAs (lncRNAs) in the pathogenesis of MPNs remains largely unexplored.

Purpose of the Study:

  • To investigate the expression and function of lncRNAs in MPN pathogenesis.
  • To elucidate the role of lnc-AC004893 in regulating the JAK2/STAT5 signaling pathway in MPNs.

Main Methods:

  • Quantitative real-time PCR (qRT-PCR) to measure lnc-AC004893 expression in MPN patients.
  • Short hairpin RNA (shRNA)-mediated knockdown of lnc-AC004893 to assess its effects on cell proliferation and signaling.
  • Western blot and co-immunoprecipitation (co-IP) to analyze protein interactions and signaling pathway modulation.
  • In vivo studies using a BaF3-JAK2V617F-transplanted mouse model.

Main Results:

  • Lnc-AC004893 was found to be significantly upregulated in MPN cells compared to normal controls.
  • Knockdown of lnc-AC004893 suppressed MPN cell proliferation, colony formation, and STAT5 phosphorylation.
  • Inhibition of lnc-AC004893 in a mouse model attenuated MPN phenotypes and improved overall survival.
  • Mechanistically, lnc-AC004893 knockdown enhanced the interaction between STAT5 and protein tyrosine phosphatase SHP1, thereby reducing STAT5 phosphorylation.

Conclusions:

  • Lnc-AC004893 plays a crucial role in MPN pathogenesis by regulating STAT5 phosphorylation through modulation of STAT5-SHP1 interactions.
  • Lnc-AC004893 represents a potential therapeutic target for MPN patients.
Keywords:
Myeloproliferative neoplasmsSHP1STAT5long noncoding RNAs

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