Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes
- Mathieu Tremblay1,7,
- Cédric S. Tremblay1,7,
- Sabine Herblot1,8,
- Peter D. Aplan2,
- Josée Hébert3,
- Claude Perreault1 and
- Trang Hoang1,4,5,6,9
- 1Institute of Research in Immunology and Cancer, University of Montreal, Montréal, Québec H3C 3J7, Canada;
- 2Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA;
- 3Banque de Cellules Leucémiques du Québec, Maisonneuve-Rosemont Hospital, Montréal, Québec H1T 2M4, Canada;
- 4Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada;
- 5Department of Biochemistry, Faculty of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada;
- 6Department of Molecular Biology, Faculty of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada
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↵7 These authors contributed equally to this work.
Abstract
Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcrβ clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.
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Footnotes
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↵9 Corresponding author.
E-MAIL trang.hoang{at}umontreal.ca; FAX (514) 343-6945.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1897910.
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Supplemental material is available at http://www.genesdev.org.
- Received December 18, 2009.
- Accepted April 12, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press