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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum Stress / drug effects
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Endoribonucleases / antagonists & inhibitors*
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Endoribonucleases / genetics
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Endoribonucleases / metabolism
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Mice
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Mice, Knockout
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Piperidines
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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Regulatory Factor X Transcription Factors
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Signal Transduction / drug effects
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism
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X-Box Binding Protein 1
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Piperidines
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Pyrazoles
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Pyrimidines
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Regulatory Factor X Transcription Factors
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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ibrutinib
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ERN1 protein, human
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Ern1 protein, mouse
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Adenine