PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia.
The development and the propagation of chronic lymphocytic leukemia (CLL) has been linked to signaling via the B-cell receptor (BCR). Protein kinase C beta (PKCbeta) is an essential signaling element of the BCR and was recently shown to be overexpressed in human CLL. We used the TCL1 transgenic mouse model to directly target PKCbeta in the development of murine CLL. TCL1 overexpression did restore the CD5(+) B-cell population that is absent in PKCbeta-deficient mice. However, PKCbeta-deleted TCL1 transgenic mice did not develop a CLL disease, suggesting a role of PKCbeta in the establishment of the malignant clone. Moreover, targeting of PKCbeta with the specific inhibitor enzastaurin led to killing of human CLL samples in vitro. We thus propose that PKCbeta may be a relevant target for the treatment of CLL.
Holler
Claudia
C
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department for Hematology, Oncology, Hemostasiology, Infectious Diseases and Rheumatology, University Hospital Salzburg, Salzburg, Austria.
Piñón
Josefina D
JD
Denk
Ursula
U
Heyder
Christoph
C
Hofbauer
Sebastian
S
Greil
Richard
R
Egle
Alexander
A
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D018956:CD5 Antigens / Q000032:analysis; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002867:Chromones / Q000494:pharmacology; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D002867:Chromones; D007211:Indoles; D009025:Morpholines; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; C504878:enzastaurin