Submitted May 5, 2006
Accepted September 27, 2006
Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity
Laura A Smit, Delfine YH Hallaert, Rene Spijker, Bart de Goeij, Annelieke Jaspers, Arnon P Kater, Marinus HJ van Oers, Carel J van Noesel, and Eric Eldering*
Academic Medical Center, Netherlands
* Corresponding author; email: e.eldering{at}amc.uva.nl.
The gradual accumulation of chronic lymphocytic leukemia (B-CLL) cells is presumed to derive from proliferation centers in lymph nodes and bone marrow. To what extent these cells possess the purported anti-apoptotic phenotype of peripheral B-CLL cells is unknown. Recently, we have described that in B-CLL samples from peripheral blood, aberrant apoptosis gene expression was not limited to protective changes but also included increased levels of pro-apoptotic BH3-only member Noxa. Here, we compare apoptosis gene profiles from peripheral blood B-CLL (n=15) with lymph node B-CLL (>90% CD5+/CD19+/CD23+ lymphocytes with Ki67+ centers; n=9). Apart from expected differences in Survivin and Bcl-xL, a prominent distinction with peripheral B-CLL cells was the decreased averaged level of Noxa in lymph nodes. Mcl-1 protein expression showed a reverse trend. Noxa expression could also be reduced in vitro by CD40 stimulation of peripheral blood B-CLL. Direct manipulation of Noxa protein levels was achieved by proteasome inhibition in B-CLL and via RNAi in model cell lines. In each instance, cell viability was directly linked with Noxa levels. These data indicate that suppression of Noxa in the lymph node environment contributes to the persistence of B-CLL at these sites and suggest that therapeutic targeting of Noxa might be beneficial.
