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SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells.

Bastien Gerby1, Cedric S Tremblay1, Mathieu Tremblay1

  • 1Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

Plos Genetics
|December 19, 2014
PubMed
Summary

Normal thymocytes can become self-renewing pre-leukemic stem cells (pre-LSCs) through SCL-LMO1 interaction, a critical step in T-cell acute lymphoblastic leukemia (T-ALL) development. NOTCH1 signaling enhances this reprogramming process, highlighting a potential therapeutic target for T-ALL.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The molecular mechanisms driving normal cell transformation into cancer stem cells are not fully understood.
  • T-cell acute lymphoblastic leukemia (T-ALL) provides a model to investigate early oncogenic events.

Purpose of the Study:

  • To define the critical initiating events in T-ALL development.
  • To identify molecular determinants of oncogenic reprogramming in thymocytes.

Main Methods:

  • Utilized genetic evidence to define interactions between oncogenic transcription factors SCL and LMO1.
  • Investigated the role of LYL1 and NOTCH1 signaling in thymocyte reprogramming.
  • Analyzed gene expression patterns in T-ALL patient samples.

Main Results:

  • SCL and LMO1 reprogram thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs) that retain T-cell differentiation capacity.
  • LYL1 cooperates with SCL-LMO1 in reprogramming; E2A inhibition is insufficient.
  • DN3 thymocytes are uniquely susceptible due to high NOTCH1 signaling, which synergizes with SCL-LMO1 via Hes1 and Myc.
  • LYL1 and LMO1/LMO2 are co-expressed in most human T-ALL subtypes.

Conclusions:

  • Acquisition of self-renewal by thymocytes is a critical early event in T-ALL genesis.
  • The SCL-LMO1-LYL1-NOTCH1 network is crucial for pre-LSC formation and may be relevant to a majority of T-ALL cases.