Different Cre transgenes initiate Sleeping-Beauty (SB) transposon-mutagenesis at distinct stages during T-cell development, causing T-ALL in mice. Distinct combinations of common insertion sites (CISs), equivalent to driver mutations, are selected for in the tumors, depending on when mutagenesis is initiated. Surprisingly, if mutagenesis is initiated late during development, at the DP stage, the resulting tumors show features of human ETP-ALL, raising the possibility that this high-risk leukemia originates from more mature cells that revert to an immature immune phenotype on transformation.