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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 &gt;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.

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