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APN Inhibitor Bestatin Induces MM Cell Differentiation Through the CD79B/BTK/STAT3 Pathway.

Xiaoke Wang1, Chunyan Fang1, Shanyu Li1

  • 1School of Pharmacy, Shandong Second Medical University, Weifang 261000, China.

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|May 27, 2026
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Summary

The aminopeptidase N (APN) inhibitor Bestatin promotes multiple myeloma (MM) cell differentiation by downregulating the CD79B/BTK pathway and activating STAT3. This offers a new strategy for combination therapies with drugs like Ixazomib.

Keywords:
BestatinCD79B/BTKdifferentiationmultiple myeloma

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Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Differentiation therapy is a promising strategy for treating multiple myeloma (MM).
  • Aminopeptidase N (APN) inhibitor Bestatin has been previously identified to promote MM cell differentiation.
  • The precise molecular mechanisms underlying Bestatin's effect on MM cell differentiation require elucidation.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Bestatin induces differentiation in multiple myeloma (MM) cells.
  • To investigate the role of the CD79B/BTK-STAT3 signaling axis in Bestatin-mediated MM cell differentiation.
  • To explore the potential of targeting this pathway for novel combination therapies in MM.

Main Methods:

  • Utilized multiple myeloma cell lines (MM1.S, U266, RPMI-8226).
  • Employed CCK-8 assays, flow cytometry, Wright-Giemsa staining, Western blotting, qRT-PCR, ELISA, APN enzymatic activity analysis, SA-β-gal staining, and bioinformatic analyses.
  • Investigated the effects of Bestatin, APN-neutralizing antibody (WM15), CD79B/BTK inhibitor (Ibrutinib), STAT3 agonist (GCDA), and Ixazomib.

Main Results:

  • Bestatin treatment induced MM cell differentiation in a concentration-dependent manner, increasing CD49e expression, immunoglobulin light chain secretion, and cellular senescence, while decreasing proliferation and APN activity.
  • Mechanistically, Bestatin downregulated the CD79B/BTK pathway, leading to STAT3 activation.
  • Inhibition of CD79B/BTK induced differentiation, STAT3 blockade abrogated Bestatin's effect, and WM15 confirmed APN's role.
  • Ibrutinib and GCDA potentiated Ixazomib's cytotoxicity, and Bestatin synergized with Ixazomib and IL-6.

Conclusions:

  • Bestatin induces multiple myeloma cell differentiation through the CD79B/BTK-STAT3 signaling axis.
  • Targeting this pathway is a promising strategy to enhance the efficacy of existing MM drugs like Ixazomib.
  • These findings provide a strong rationale for developing novel combination therapies for multiple myeloma.