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Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia

Sofiane Berrazouane1, Marc Boisvert1, Suzanne Salti2

  • 1Division of Immune and Infectious Diseases, CHU de Québec-Université Laval Research Center, Quebec city, Canada.

Cell Death & Disease
|May 3, 2019
PubMed

Insights

Beta-1 integrins promote chemoresistance in T-cell acute lymphoblastic leukemia (T-ALL) by enhancing drug efflux. Blocking these integrins sensitizes leukemia cells to doxorubicin, suggesting a new therapeutic target for T-ALL.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Cell adhesion to the extracellular matrix (ECM) is increasingly recognized for its role in cancer chemoresistance.
  • Beta-1 integrins are expressed by leukemic T cells and mediate interactions with the ECM, but their specific role in T-cell acute lymphoblastic leukemia (T-ALL) chemoresistance is unclear.

Purpose of the Study:

  • To investigate the role of beta-1 integrins in chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL).
  • To explore the underlying mechanisms of beta-1 integrin-mediated chemoresistance and identify potential therapeutic targets.

Main Methods:

  • Utilized human T-ALL cell lines and primary blasts cultured in 3D matrices (Matrigel, collagen type I gel).
  • Employed beta-1 integrin neutralizing antibodies, doxorubicin treatment, and xenograft models in mice.
  • Investigated doxorubicin efflux, ABCC1 drug transporter activation, and the involvement of FAK-related proline-rich tyrosine kinase 2 (PYK2) signaling.

Main Results:

  • Interaction with 3D matrices via beta-1 integrin conferred doxorubicin resistance in T-ALL cells.
  • Blocking beta-1 integrin sensitized T-ALL cells to doxorubicin, reduced leukemic burden, and improved survival in xenograft models.
  • Beta-1 integrin interaction enhanced chemoresistance by promoting doxorubicin efflux via ABCC1 activation and PYK2 signaling.

Conclusions:

  • Beta-1 integrin signaling plays a significant role in mediating chemoresistance in T-cell acute lymphoblastic leukemia.
  • Targeting the beta-1 integrin pathway presents a promising therapeutic strategy to overcome doxorubicin resistance and prevent relapse in T-ALL.

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