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Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas

Authors' Affiliations: ¹ Institute for Cancer Genetics-Columbia University, Departments of ² Pathology, and ³ Pediatrics, Columbia University Medical Center, New York, New York

Requests for reprints: Adolfo Ferrando, Columbia University Medical Center, Pathology and Pediatrics, 1130 St. Nicholas Avenue, ICRC 505A, New York, NY 10032. Phone: 212-851-4611; Fax: 212-851-5256; E-mail: af2196{at}columbia.edu.

Abstract

The identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias and lymphomas (T-ALL) has brought much interest in inhibiting NOTCH1 signaling as therapeutic target in this disease. Small-molecule inhibitors of the -secretase complex, which mediates a critical proteolytic cleavage required for NOTCH1 activation, hold the promise of becoming an effective molecular therapy against relapsed and refractory T-ALL. Recent progress in the elucidation of the transcriptional regulatory networks downstream of oncogenic NOTCH1 has uncovered a central role of NOTCH1 signaling in promoting leukemic cell growth and revealed an intricate circuitry that connects NOTCH1 signaling with MYC and the PI3K-AKT signaling pathway. The identification of the downstream effector pathways controlled by NOTCH1 should pave the way for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL.

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