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This is an open‐access article distributed under the terms of the Creative Commons Attribution License.-- et al., The incidence, malignancy and treatment resistance of many types of human B-cell leukaemias (B-ALL) are directly related to patient age. A major obstacle to elucidate the contribution of age to the development and evolution of leukaemias is the lack of appropriate mouse models where precise control of the timing of oncogene expression is possible. Here we present proof-of-principle experiments showing how a conditional transgenic mouse model of BCR-ABLp190-driven B-ALL offers the opportunity to test the hypothesis that the age of the leukemic cells-of-origin of B-ALL influences B-ALL malignancy. B-ALLs generated from 12- and 20-month-old progenitors gave rise to a more invasive B-ALL than the one developed from 4-month old precursors. This was evidenced by survival analysis revealing the increased malignancy of B-ALLs generated from 20 or 12-month-old transformed progenitors compared with the 4-month equivalents (median survival of 88 days versus 50.5 and 33 days, respectively). Our study shows that the age of target cells at the time of transformation affects B-ALL malignancy., Research in ISG group was partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (Proyecto Biomedicina 2009- 2010 to ISG), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon. CVD research is supported by Junta de Castilla y León (proyecto de investigación en biomedicina SAN/39/2010). ISG is an API lab of the EuroSyStem project. Research at C.C.´s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI080164), CSIC P.I.E., Junta de Castilla y León (SA060A09 and proyecto Biomedicina 2009-2010) and from an institutional grant from the Fundación Ramón Areces. F.A-J. was supported by an FPU fellowship from the Spanish Ministerio de Ciencia e Innovacion.