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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3898-3906.
Prepublished online as a Blood First Edition Paper on August 23, 2005; DOI 10.1182/blood-2005-01-0355.
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NEOPLASIA
Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies
Patrick A. Zweidler-McKay,
Yiping He,
Lanwei Xu,
Carlos G. Rodriguez,
Fredrick G. Karnell,
Andrea C. Carpenter,
Jon C. Aster,
David Allman, and
Warren S. Pear
From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; the Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA; the Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA; the Divisions of Hematology and Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
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.
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