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A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia

Daniel Herranz1, Alberto Ambesi-Impiombato1, Teresa Palomero2

  • 1Institute for Cancer Genetics, Columbia University, New York, New York, USA.

Nature Medicine
|September 8, 2014
PubMed

Insights

Researchers discovered a novel MYC enhancer, N-Me, crucial for NOTCH1-driven T cell acute lymphoblastic leukemia (T-ALL). This long-range element, duplicated in T-ALL, drives MYC expression and is vital for thymocyte development.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Focus on protein-coding genes for cancer driver lesions overlooks intergenic abnormalities.
  • The role of non-coding regulatory elements in oncogenesis is increasingly recognized.

Purpose of the Study:

  • To identify and characterize novel genetic lesions in intergenic regions of human cancers.
  • To investigate the regulatory mechanisms driving MYC expression in T cell acute lymphoblastic leukemia (T-ALL).

Main Methods:

  • Identification of a novel long-range enhancer (N-Me) using genomic analysis.
  • Reporter assays to assess N-Me's regulatory function on MYC expression.
  • Analysis of N-Me knockout mice to determine its role in thymocyte development and T-ALL.

Main Results:

  • A new long-range MYC enhancer, N-Me, controlled by NOTCH1, was identified.
  • N-Me is targeted by chromosomal duplications in human T-ALL and interacts with the MYC promoter.
  • N-Me knockout mice exhibit defects in thymocyte development and resistance to NOTCH1-induced T-ALL.

Conclusions:

  • N-Me is a critical long-range oncogenic enhancer in T-ALL pathogenesis.
  • The NOTCH1-MYC regulatory axis is essential for T cell transformation and represents a potential therapeutic target in T-ALL.

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