Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes

Mathieu Tremblay, Cedric Tremblay, Sabine Herblot, Peter D Aplan, Josee Hebert, Claude Perreault, Trang Hoang

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75 Citations (Scopus)

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 Tcr? 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. ? 2010 by Cold Spring Harbor Laboratory Press.
Original languageEnglish
Pages (from-to)1093 - 1105
Number of pages13
JournalGenes & Development
Volume24
Issue number11
DOIs
Publication statusPublished - 2010
Externally publishedYes

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