1. Academic Validation
  2. Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival

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

  • J Clin Invest. 2014 Jun;124(6):2585-98. doi: 10.1172/JCI73448.
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
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-107400
    98.69%, IRE1 Inhibitor