BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgVH unmutated chronic lymphocytic leukemia (CLL) cells

A Guarini, S Chiaretti, S Tavolaro… - Blood, The Journal …, 2008 - ashpublications.org
A Guarini, S Chiaretti, S Tavolaro, R Maggio, N Peragine, F Citarella, MR Ricciardi
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
Chronic lymphocytic leukemia (CLL) patients exhibit a variable clinical course. To
investigate the association between clinicobiologic features and responsiveness of CLL
cells to anti-IgM stimulation, we evaluated gene expression changes and modifications in
cell-cycle distribution, proliferation, and apoptosis of IgVH mutated (M) and unmutated (UM)
samples upon BCR cross-linking. Unsupervised analysis highlighted a different response
profile to BCR stimulation between UM and M samples. Supervised analysis identified …
Abstract
Chronic lymphocytic leukemia (CLL) patients exhibit a variable clinical course. To investigate the association between clinicobiologic features and responsiveness of CLL cells to anti-IgM stimulation, we evaluated gene expression changes and modifications in cell-cycle distribution, proliferation, and apoptosis of IgVH mutated (M) and unmutated (UM) samples upon BCR cross-linking. Unsupervised analysis highlighted a different response profile to BCR stimulation between UM and M samples. Supervised analysis identified several genes modulated exclusively in the UM cases upon BCR cross-linking. Functional gene groups, including signal transduction, transcription, cell-cycle regulation, and cytoskeleton organization, were up-regulated upon stimulation in UM cases. Cell-cycle and proliferation analyses confirmed that IgM cross-linking induced a significant progression into the G1 phase and a moderate increase of proliferative activity exclusively in UM patients. Moreover, we observed only a small reduction in the percentage of subG0/1 cells, without changes in apoptosis, in UM cases; contrariwise, a significant increase of apoptotic levels was observed in stimulated cells from M cases. These results document that a differential genotypic and functional response to BCR ligation between IgVH M and UM cases is operational in CLL, indicating that response to antigenic stimulation plays a pivotal role in disease progression.
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