Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice.
Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ~ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (Eμ-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 Eμ-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 Igα and Igβ, 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.
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Crystina L
CL
Kriss
Javier A
JA
Pinilla-Ibarz
Adam W
AW
Mailloux
John J
JJ
Powers
Chih-Hang Anthony
CH
Tang
Chang Won
CW
Kang
Nicola
N
Zanesi
Pearlie K
PK
Epling-Burnette
Eduardo M
EM
Sotomayor
Carlo M
CM
Croce
Juan R
JR
Del Valle
Chih-Chi Andrew
CC
Hu
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; D051562:Proto-Oncogene Proteins c-bcr