Survival of leukemic B cells promoted by engagement of the antigen receptor.
Chronic lymphocytic leukemia (CLL) is an incurable leukemia characterized by the slow but progressive accumulation of cells in a CD5+ B-cell clone. Like the nonmalignant counterparts, B-1 cells, CLL cells often express surface immunoglobulin with the capacity to bind autologous structures. Previously there has been no established link between antigen-receptor binding and inhibition of apoptosis in CLL. In this work, using primary CLL cells from untreated patients with this disease, it is demonstrated that engagement of surface IgM elicits a powerful survival program. The response includes inhibition of caspase activity, activation of NF-kappaB, and expression of mcl-1, bcl-2, and bfl-1 in the tumor cells. Blocking phosphatidylinositol 3-kinase (PI3-K), a critical mediator of signals through the antigen receptor, completely abrogated mcl-1 induction and impaired survival in the stimulated cells. These data support the contention that CLL cell survival is promoted by antigen for which the malignant clone has affinity, and suggest that pharmacologic interference with antigen-receptor-derived signals has potential for therapy in patients with CLL.
Bernal
A
A
Immunology Program, Weill Graduate School of Medical Sciences of Cornell University, and Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Pastore
R D
RD
Asgary
Z
Z
Keller
S A
SA
Cesarman
E
E
Liou
H C
HC
Schattner
E J
EJ
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D019013:CD40 Antigens / Q000502:physiology; D018956:CD5 Antigens / Q000032:analysis; D002470:Cell Survival; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007075:Immunoglobulin M / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D051020:bcl-X Protein
D019013:CD40 Antigens; D018956:CD5 Antigens; D007075:Immunoglobulin M; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human