Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies.
Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.
Zweidler-McKay
Patrick A
PA
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 611 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA.
He
Yiping
Y
Xu
Lanwei
L
Rodriguez
Carlos G
CG
Karnell
Fredrick G
FG
Carpenter
Andrea C
AC
Aster
Jon C
JC
Allman
David
D
Pear
Warren S
WS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch