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 Blood, 1 August 2008, Vol. 112, No. 3, pp. 782-792.
Prepublished online as a Blood First Edition Paper on May 16, 2008; DOI 10.1182/blood-2007-12-127688.

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NEOPLASIA

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

Anna Guarini1, Sabina Chiaretti1, Simona Tavolaro1, Roberta Maggio1, Nadia Peragine1, Franca Citarella2, Maria Rosaria Ricciardi1, Simona Santangelo1, Marilisa Marinelli1, Maria Stefania De Propris1, Monica Messina1, Francesca Romana Mauro1, Ilaria Del Giudice1, and Robert Foà1

Divisions of 1 Hematology, and 2 Genetics, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy

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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