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Clin Cancer Res. 2008 Sep 1;14(17):5314-7. doi: 10.1158/1078-0432.CCR-07-4864.

Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-cell acute lymphoblastic leukemias and lymphomas.

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1
Institute for Cancer Genetics-Columbia University, Columbia University Medical Center, New York, New York 10032, USA.

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 gamma-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.

PMID:
18765521
PMCID:
PMC2577004
DOI:
10.1158/1078-0432.CCR-07-4864
[Indexed for MEDLINE]
Free PMC Article
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