Transgenic mice for MTCP1 develop T-cell prolymphocytic leukemia.
Transgenic mice for MTCP1 develop T-cell prolymphocytic leukemia.
复制标题
MTCP1 转基因小鼠患上 T 细胞幼淋巴细胞白血病。
作者：
C. Gritti;H. Dastot;J. Soulier;A. Janin;M. Daniel;A. Madani;G. Grimber;P. Briand;F. Sigaux;M. Stern
T细胞幼淋巴细胞白血病（T-PLL）是一种罕见的成熟T细胞白血病，与涉及MTCP 1或TCL 1基因的染色体重排有关。这些基因编码两个同源蛋白，p13（MTCP 1）和p14（TCL 1），它们与其他已知蛋白没有相似性。为了确定MTCP 1的致癌作用，产生了在CD 2调节区控制下的MTCP 1转基因小鼠（CD 2-p13小鼠）。出生后第一年内未发现异常。在一组48只15至20个月龄的CD 2-p13小鼠中寻找转基因的晚期效应，这些小鼠来自3只独立的创始人。在三个转基因株系中发生的类血友病的特征在于具有不规则核的淋巴细胞、独特且突出的核仁、浓缩的染色质、缺乏颗粒的嗜碱性细胞质和成熟T细胞的免疫表型。Tcrb重排的分子特征表明这些人群的单克隆起源。队列的组织学分析显示早期脾脏和肝脏浸润，而淋巴细胞增多和髓质浸润很少发现。在H2-匹配的动物中这些增殖的植入证明了它们的恶性性质。在F3、F4和F7系中，20个月时疾病的累积发病率分别为100%、50%和21%，对照组为零。如通过蛋白质印迹法在转基因系中估计的，转基因的表达水平与肿瘤发病率相关，其中在F3小鼠中发现p13（MTCP 1）的最高表达。CD 2-p13转基因小鼠发生了类似于人类T-PLL的血液病。这些数据表明，p13（MTCP 1）是一种癌蛋白和CD 2-p13转基因小鼠代表了成熟的T-PLL的第一个动物模型。
T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements implicating MTCP1 or TCL1 genes. These genes encode two homologous proteins, p13(MTCP1) and p14(TCL1), which share no similarity with other known protein. To determine the oncogenic role of MTCP1, mice transgenic for MTCP1 under the control of CD2 regulatory regions (CD2-p13 mice) were generated. No abnormality was detected during the first year after birth. A late effect of the transgene was searched for in a cohort of 48 CD2-p13 mice aged 15 to 20 months, issued from 3 independent founders. Lymphoid hemopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus, a unique and prominent nucleolus, condensed chromatin, a basophilic cytoplasm devoid of granules, and an immunophenotype of mature T cells. The molecular characterization of Tcrb rearrangements demonstrated the monoclonal origin of these populations. Histopathological analysis of the cohort demonstrated early splenic and hepatic infiltrations, whereas lymphocytosis and medullar infiltrations were found infrequently. The engraftment of these proliferations in H2-matched animals demonstrated their malignant nature. Cumulative incidence of the disease at 20 months was 100%, 50%, and 21% in F3, F4, and F7 lines, respectively, and null in the control group. The level of expression of the transgene, as estimated by Western blotting in the transgenic lines correlated with the tumoral incidence, with the highest expression of p13(MTCP1) being found in F3 mice. CD2-p13 transgenic mice developed an hemopathy similar to human T-PLL. These data demonstrate that p13(MTCP1) is an oncoprotein and that CD2-p13 transgenic mice represent the first animal model for mature T-PLL.