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

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

Research output: Contribution to journalArticle

94 Scopus citations

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 membranebound 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.

Original languageEnglish (US)
Pages (from-to)2585-2598
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014

ASJC Scopus subject areas

  • Medicine(all)

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