Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Inhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival
Chih-Hang Anthony Tang, … , Juan R. Del Valle, Chih-Chi Andrew Hu
Chih-Hang Anthony Tang, … , Juan R. Del Valle, Chih-Chi Andrew Hu
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2585-2598. https://doi.org/10.1172/JCI73448.
View: Text | PDF
Research Article Oncology

Inhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival

  • Text
  • PDF
Abstract

Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress–associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor–bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma.

Authors

Chih-Hang Anthony Tang, Sujeewa Ranatunga, Crystina L. Kriss, Christopher L. Cubitt, Jianguo Tao, Javier A. Pinilla-Ibarz, Juan R. Del Valle, Chih-Chi Andrew Hu

×

Figure 5

IRE-1 inhibitors with masked aldehyde moieties potently suppress XBP-1s expression and leukemic growth.

Options: View larger image (or click on image) Download as PowerPoint
IRE-1 inhibitors with masked aldehyde moieties potently suppress XBP-1s ...
(A) WaC3 CLL cells were treated with indicated compounds for 24 hours and lysed for RNA extraction. Human unspliced XBP1 (XBP1u), spliced XBP1 (XBP1s), and actin were detected by RT-PCR using specific primers. Data are representative of 3 experiments. (B) Mouse B cells were stimulated with LPS for 48 hours to allow for XBP-1s expression, and then treated with indicated inhibitors for 24 hours. Lysates were immunoblotted for XBP-1s and p97. Data are representative of 3 experiments. (C) LPS-stimulated B cells were treated with 0, 1.25, 2.5, 5, 10, 20, 40, 80, or 160 mM B-H09 for 24 hours. Equal amounts of lysates were immunoblotted for XBP-1s. The XBP-1s protein band intensity was determined using ImageJ. The percentage of inhibition was determined by comparing with the untreated group. Data from 3 experiments were plotted as mean ± SEM. (D) Mouse CD3–IgM+CD5+ Eμ-TCL1 CLL cells were treated with DMSO or indicated inhibitors for 3 days and subjected to XTT assays. Percentages of growth were determined by comparing inhibitor-treated with DMSO-treated groups. Data from 4 identical experimental groups were plotted as mean ± SD. Results are representative of 3 experiments. (E and F) Primary CLL cells from 2 human patients were treated with DMSO or indicated inhibitors (20 μM), subjected to XTT assays, and similarly analyzed. Data from 4 identical experimental groups were plotted as mean ± SD. Results are representative of 3 experiments.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts