Asnafi Vahid, Beldjord Kheira, Libura Marta, Villarese Patrick, Millien Corrine, Ballerini Paola, Kuhlein Emilienne, Lafage-Pochitaloff Marina, Delabesse Eric, Bernard Olivier, Macintyre Elizabeth
Necker-Enfants-Malades and Trousseau, Assistance Publique-Hopitaux de Paris, INSERM EMIU210 and Université Paris V, Hôpital Purpan, Toulouse, France.
Blood. 2004 Dec 15;104(13):4173-80. doi: 10.1182/blood-2003-11-3944. Epub 2004 Mar 30.
Postnatal thymic involution occurs progressively throughout the first 3 decades of life. It predominantly affects T-cell receptor (TCR) alphabeta-lineage precursors, with a consequent proportional increase in multipotent thymic precursors. We show that T-acute lymphoblastic leukemias (T-ALLs) demonstrate a similar shift with age from predominantly TCR expressing to an immature (IM0/delta/gamma) 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 alphabeta-lineage oncogenes, whereas HOX11L2 expression identifies an intermediate alphabeta/gammadelta-lineage stage of maturation arrest. In keeping with preferential alphabeta-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 alphabeta-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/delta/gamma 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.
出生后胸腺退化在生命的前三十年中逐渐发生。它主要影响T细胞受体（TCR）αβ谱系前体，从而导致多能胸腺前体成比例增加。我们发现，T急性淋巴细胞白血病（T-ALL）随着年龄增长也表现出类似的转变，即从主要表达TCR转变为不成熟（IM0/δ/γ）阶段的成熟停滞。半数病例表现出HOX11、HOX11L2、SIL-TAL1或CALM-AF10失调，每种失调都与特定的、不依赖年龄的成熟停滞阶段相关。HOX11和SIL-TAL代表αβ谱系致癌基因，而HOX11L2的表达则确定了成熟停滞的中间αβ/γδ谱系阶段。与αβ谱系的优先退化一致，SIL-TAL1和HOX11L2失调的发生率随年龄下降。相比之下，HOX11失调变得更加频繁，提示潜伏期更长。TAL1/LMO1失调在αβ谱系T-ALL中更常见，在儿童中主要是由于SIL-TAL1重排，而在青少年和成人中则是由于目前未知的机制。LMO2与LYL1共表达更为频繁，主要在IM0/δ/γ成人病例中，而不是与TAL1共表达。这些与年龄相关的表型和致癌途径变化可能反映了胸腺中处于恶性转化风险的细胞群的渐进性变化。
