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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.
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Research Article Oncology

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

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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

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Figure 2

XBP-1 deficiency compromises activation of the BCR and synthesis of secretory IgM in Eμ-TCL1 B cells.

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XBP-1 deficiency compromises activation of the BCR and synthesis of secr...
(A) XBP-1KO/Eμ-TCL1 B cells respond ineffectively to activation via the BCR. XBP-1WT/Eμ-TCL1 and XBP-1KO/Eμ-TCL1 B cells were treated with LPS for 3 days, stimulated with F(ab′)2 anti-mouse IgM to crosslink the BCR for indicated times, and lysed for analysis of indicated proteins by immunoblots. (B and C) WT B cells and CLL cells were isolated from 12-month-old WT, XBP-1WT/Eμ-TCL1 and XBP-1KO/Eμ-TCL1 mice. Purified cells were radiolabeled for 15 minutes, chased for indicated times, and lysed. Intracellular and extracellular IgM were immunoprecipitated from lysates (B) and culture medium (C), respectively, using an anti-κ antibody. Immunoprecipitates were analyzed on an SDS-PAGE gel. Data are representative of 3 independent experiments.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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