Postnatal thymic involution occurs progressively throughout the first 3 decades of life. It predominantly affects T-cell receptor (TCR) ␣␤-lineage precursors, with a consequent proportional increase in multipotent thymic precursors. We show that T-acute lymphoblastic leukemias (TALLs) demonstrate a similar shift with age from predominantly TCR expressing to an immature (IM0/␦/␥) stage of maturation arrest. Half demonstrate HOX11, HOX11L2, SIL-TAL1, or CALM-AF10 deregulation, with each being associated with a specific, age-independent stage of maturation arrest. HOX11 and SIL-TAL represent ␣␤-lineage oncogenes, whereas HOX11L2 expression identifies an intermediate ␣␤/␥␦-lineage stage of maturation arrest. In keeping with preferential ␣␤-lineage involution, the incidence of SIL-TAL1 and HOX11L2 deregulation decreased with age. In contrast, HOX11 deregulation became more frequent, suggesting longer latency. TAL1/LMO1 deregulation is more frequent in ␣␤-lineage T-ALL, when it is predominantly due to SIL-TAL1 rearrangements in children but to currently unknown mechanisms in adolescents and adults. LMO2 was more frequently coexpressed with LYL1, predominantly in IM0/␦/␥ adult cases, than with TAL1. These age-related changes in phenotype and oncogenic pathways probably reflect progressive changes in the thymic population at risk of malignant transformation. ( IntroductionHuman T lymphocytes are derived from pluripotent hemopoietic progenitors that migrate throughout life from the bone marrow to the thymus, where the majority of T-cell development occurs. Progressive thymic atrophy during the first 2 to 3 decades of life leads to a reduction of thymic mass and, to a lesser extent, function. 1,2 The earliest thymic progenitor corresponds to a minor (Ͻ 1% of thymocytes) sCD3 Ϫ , CD4/CD8 double-negative (DN) population that does not alter with age. [3][4][5][6] In the neonatal murine thymus, the majority of lymphocytes belong to the ␣␤ lineage; successful T-cell receptor ␤ (TCR␤) rearrangement in a DN precursor in the presence of pT␣ allows expression of the pre-TCR in association with CD3, progression to the CD4/8 double-positive (DP) stage, and massive thymocyte expansion, a process known as ␤ selection 7 ; this population diminishes markedly with age, with a consequent increase in the proportion of DN cells.T-acute lymphoblastic leukemias (T-ALLs) correspond to a heterogeneous group of acute leukemias arrested at various stages of lymphoid development. They account for 10% to 15% of pediatric and 25% of adult ALLs, with a relatively constant incidence up to the third decade. [8][9][10] Recognized T-ALL oncogenic pathways include transcriptional deregulation by juxtapositioning to one of the TCR loci, resulting in transcriptional deregulation of genes such as HOX11/TLX1, LMO2, LMO1, LYL1, and TAL1/SCL, each of which is present in less than 10% of cases. [11][12][13][14][15][16][17][18][19][20][21][22] More common genetic defects in T-ALL are submicroscopic deletions of p16/INK4 in 40% to 80% 23,24 or SIL-TAL1 in 10% to ...