Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia

Author:

Demarest Renée M.12,Dahmane Nadia2,Capobianco Anthony J.12

Affiliation:

1. Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and University of Miami Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL; and

2. Molecular and Cellular Oncogenesis, Wistar Institute, Philadelphia, PA

Abstract

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic neoplasm characterized by malignant expansion of immature T cells. Activated NOTCH (NotchIC) and c-MYC expression are increased in a large percentage of human T-ALL tumors. Furthermore, c-MYC has been shown to be a NOTCH target gene. Although activating mutations of Notch have been found in human T-ALL tumors, there is little evidence that the c-MYC locus is altered in this neoplasm. It was previously demonstrated that Notch and c-Myc–regulated genes have a broadly overlapping profile, including genes involved in cell cycle progression and metabolism. Given that Notch and c-Myc appear to function similarly in T-ALL, we sought to determine whether these two oncogenes could substitute for each other in T-ALL tumors. Here we report that NOTCHIC is able to maintain T-ALL tumors formed in the presence of exogenous NOTCHIC and c-MYC when exogenous c-MYC expression is extinguished. In contrast, c-MYC is incapable of maintaining these tumors in the absence of NOTCHIC. We propose that failure of c-MYC to maintain these tumors is the result of p53-mediated apoptosis. These results demonstrate that T-ALL maintenance is dependent on NOTCHIC, but not c-MYC, demonstrating that NOTCH is oncogenic dominant in T-ALL tumors.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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