Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of NOTCH signaling

Andrew P. Weng, Yunsun Nam, Michael S. Wolfe, Warren S. Pear, James D. Griffin, Stephen C. Blacklow, Jon C. Aster

Research output: Contribution to journalArticle

306 Scopus citations

Abstract

Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.

Original languageEnglish (US)
Pages (from-to)655-664
Number of pages10
JournalMolecular and cellular biology
Volume23
Issue number2
DOIs
StatePublished - Jan 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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