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BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling

Chunyan Gu1,2,3, Hailin Peng4, Yue Lu5

  • 1The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China.

Oncotarget
|September 17, 2017
PubMed

Insights

Bruton

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Bruton's tyrosine kinase (BTK) is implicated in multiple myeloma stem cell (MMSC) self-renewal and drug resistance.
  • Cellular senescence is a state of irreversible growth arrest crucial in tumor suppression.

Purpose of the Study:

  • To investigate the role of elevated Bruton's tyrosine kinase (BTK) in suppressing multiple myeloma (MM) cellular senescence.
  • To explore BTK as a potential therapeutic target for MM.

Main Methods:

  • Immunohistochemistry (IHC) and chromosomal analysis of MM patient samples.
  • BTK knockdown using shRNA and overexpression in MM cells and mouse embryonic fibroblast cells (MEFs).
  • Cell cycle analysis, SA-β-gal staining, clonogenicity assays, and in vivo tumorigenicity studies.
  • Mechanism studies involving AKT signaling pathway and RB activity.

Main Results:

  • Increased BTK expression and chromosomal gain observed in MM samples compared to normal controls.
  • High BTK expression in MM patients correlates with poor prognosis in TT2 and TT3 cohorts.
  • BTK knockdown induced MM cellular senescence, cell cycle arrest, and reduced clonogenicity.
  • BTK activation of AKT signaling down-regulated P27 and hindered RB activity, contributing to senescence resistance.
  • BTK inhibitor CGI-1746 induced MM cellular senescence and inhibited tumor growth in vivo.

Conclusions:

  • BTK plays a novel role in promoting MM cell growth by suppressing cellular senescence.
  • Targeting BTK with inhibitors like CGI-1746 demonstrates significant therapeutic potential in preclinical models of MM.
  • BTK represents a promising therapeutic target for multiple myeloma treatment.
Keywords:
AKTBTKCGI-1746multiple myelomasenescence

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