Abstract
Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia afflicting the Western world. Unlike other more aggressive leukemias and lymphomas, CLL B-cells do not divide at a high rate and expansion of the malignant clone appears to be due to underlying defect in apoptosis.
Elevated levels of anti-apoptotic Bcl-2 are thought to be involved in the pathogenesis of CLL. The activity of Bcl-2 can be modulated my interactions with other cellular proteins. Recently, orphan nuclear receptor TR3 (nur77) was shown to exit the nucleus, bind Bcl-2, and convert Bcl-2 into a killer protein (
Lin, et al.,
). We evaluated the expression of TR3 by immunoblotting in CLL B-cells specimens. High levels of TR3 protein were present in 8 of 8 CLL patient specimens. Subcellular fractionation studies showed predominately nuclear localization of TR3 in 2 of 2 CLL specimens examined. Because Akt is known to regulate TR3 activity in the nucleus (CELL
, 116
:527
, 2004
Pekarsky, et al.,
), we also examined the expression of the Akt regulator, Tcl-1. The Tcl-1 protein was expressed in the majority of CLL samples and at high levels in 8 of 16 CLL specimens, correlating with ZAP70-positivity. In gene transfection experiments using tumor cell lines, over-expression of Tcl-1 inhibited nuclear export of TR3, as determined by immunofluorescence confocal microscopy. We propose a model in which expression of the oncogene Tcl-1 in CLL B-cells (perhaps related to ZAP70 expression) modulates nuclear Akt activity, in turn suppressing TR3 function, and thus reducing activity of the TR3-mediated pathway for conversion of Bcl-2 from protector to killer. This hypothesis requires further experimental testing.Proc. Natl. Acad. Sci.
98
:3690
, 2001
Author notes
Corresponding author
2005, The American Society of Hematology
2004
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