Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity.
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 antiapoptotic 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 proapoptotic 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 be reduced also 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.
Smit
Laura A
LA
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Hallaert
Delfine Y H
DY
Spijker
René
R
de Goeij
Bart
B
Jaspers
Annelieke
A
Kater
Arnon P
AP
van Oers
Marinus H J
MH
van Noesel
Carel J M
CJ
Eldering
Eric
E
D017209:Apoptosis / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D014407:Tumor Cells, Cultured
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2