title: BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells.
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 IgV(H) 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 G(1) phase and a moderate increase of proliferative activity exclusively in UM patients. Moreover, we observed only a small reduction in the percentage of subG(0/1) 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 IgV(H) M and UM cases is operational in CLL, indicating that response to antigenic stimulation plays a pivotal role in disease progression.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Simona
authors.initials: S
authors.lastname: Tavolaro
authors.forename: Roberta
authors.initials: R
authors.lastname: Maggio
authors.forename: Nadia
authors.initials: N
authors.lastname: Peragine
authors.forename: Franca
authors.initials: F
authors.lastname: Citarella
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.forename: Simona
authors.initials: S
authors.lastname: Santangelo
authors.forename: Marilisa
authors.initials: M
authors.lastname: Marinelli
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: De Propris
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Mauro
authors.forename: Ilaria
authors.initials: I
authors.lastname: Del Giudice
authors.forename: Robert
authors.initials: R
authors.lastname: Foà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism*; D007135:Immunoglobulin Variable Region; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell