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Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell

Ji-Lin Chen1, Pei-Yi Chu2,3,4, Chun-Teng Huang5,6

  • 1Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan.

Molecular Medicine (Cambridge, Mass.)
|August 8, 2022
PubMed
Abstract

Insights

Targeting protein phosphatase SHP-1 with agonists shows therapeutic potential for diffuse large B cell lymphoma (DLBCL). SHP-1 agonists reduced tumor growth and promoted apoptosis by inhibiting B cell receptor signaling.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Diffuse large B cell lymphoma (DLBCL) is an aggressive, heterogeneous non-Hodgkin's lymphoma.
  • B cell receptor (BCR) signaling is a key pathway in DLBCL and a potential drug target.
  • Protein phosphatase SHP-1 has a tumor-suppressive role by negatively regulating oncogenic tyrosine kinases.

Purpose of the Study:

  • To evaluate the therapeutic potential of SHP-1 agonists in DLBCL.
  • To investigate the mechanism of SHP-1 action in DLBCL cells.
  • To compare the efficacy of SHP-1 agonists with a Bruton's tyrosine kinase (BTK) inhibitor.

Main Methods:

  • Immunohistochemical staining for SHP-1 expression.
  • SHP-1 phosphatase activity assays.
  • In vitro studies including MTT assays, western blot analysis, and apoptosis assays.
  • In vivo studies using xenograft models.

Main Results:

  • SHP-1 agonists demonstrated potent anti-tumor effects in DLBCL xenografts, outperforming ibrutinib.
  • SHP-1 expression was detected in 76% of DLBCL samples.
  • SHP-1 agonists reduced DLBCL cell proliferation and induced apoptosis by downregulating BCR signaling, specifically p-Lyn.
  • SHP-1 agonists increased SHP-1 activity and downregulated p-Lyn in vivo.

Conclusions:

  • SHP-1 negatively regulates Lyn phosphorylation.
  • Targeting the SHP-1/p-Lyn pathway with SHP-1 agonists represents a promising therapeutic strategy for DLBCL treatment.
Keywords:
ApoptosisDiffuse large B cell lymphomaSHP-1

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