Journal article
Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice
Blood, Vol.120(5), pp.1027-1038
08/02/2012
DOI: 10.1182/blood-2011-11-394346
PMCID: PMC3680046
PMID: 22692508
Abstract
Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in similar to 90% of human CLL. Transgenic expression of TCL1 in murine B cells (E mu-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in E mu-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Ig alpha and Ig beta, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL. (Blood. 2012;120(5):1027-1038)
Details
- Title: Subtitle
- Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice
- Creators
- Crystina L. Kriss - Moffitt Cancer CenterJavier A. Pinilla-Ibarz - Moffitt Cancer CenterAdam W. Mailloux - Moffitt Cancer CenterJohn J. Powers - Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33612 USAChih-Hang Anthony Tang - Moffitt Cancer CenterChang Won Kang - Moffitt Cancer CenterNicola Zanesi - The Ohio State UniversityPearlie K. Epling-Burnette - Moffitt Cancer CenterEduardo M. Sotomayor - Moffitt Cancer CenterCarlo M. Croce - The Ohio State UniversityJuan R. Del Valle - Moffitt Cancer CenterChih-Chi Andrew Hu - Moffitt Cancer Center
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.120(5), pp.1027-1038
- DOI
- 10.1182/blood-2011-11-394346
- PMID
- 22692508
- PMCID
- PMC3680046
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Publisher
- Amer Soc Hematology
- Number of pages
- 12
- Grant note
- P01CA081534 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 93-032-16 / Institutional Research Grant from the American Cancer Society Miles for Moffitt Foundation Funds
- Language
- English
- Date published
- 08/02/2012
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297330902771
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