Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA.
Sci Rep. 2023 May 9;13(1):7490. doi: 10.1038/s41598-023-33949-8.
Loss of function in the tumor suppressor gene TP53 is the most common alteration seen in human cancer. In mice, P53 deletion in all cells leads predominantly to the development of T-cell lymphomas, followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of P53 in the hematopoietic system, we generated and analyzed two different mouse models deficient for P53. A pan-hematopoietic P53 deletion mouse was created using Vav1-Cre based deletion; and a B-cell-specific deletion mouse was created using a CD19-Cre based deletion. The Vav1-P53CKO mice predominantly developed T-cell malignancies in younger mice, and myeloid malignancies in older mice. In T-cell malignancies, there was accelerated thymic cell maturation with overexpression of Notch1 and its downstream effectors. CD19-P53CKO mice developed marginal zone expansion in the spleen, followed by marginal zone lymphoma, some of which progressed to diffuse large B-cell lymphomas. Interestingly, marginal zone and diffuse large B-cell lymphomas had a unique gene expression signature characterized by activation of the PI3K pathway, compared with wild type marginal zone or follicular cells of the spleen. This study demonstrates lineage specific P53 deletion leading to distinct phenotypes secondary to unique gene expression programs set in motion.
抑癌基因 TP53 的失活是人类癌症中最常见的改变。在小鼠中，所有细胞中 P53 的缺失主要导致 T 细胞淋巴瘤的发展，随后是 B 细胞淋巴瘤、肉瘤和畸胎瘤。为了剖析 P53 在造血系统中的作用，我们生成并分析了两种不同的 P53 缺失小鼠模型。一种是使用 Vav1-Cre 为基础的缺失来实现的全造血细胞 P53 缺失小鼠；另一种是使用 CD19-Cre 为基础的缺失来实现的 B 细胞特异性缺失小鼠。Vav1-P53CKO 小鼠在年轻小鼠中主要发展 T 细胞恶性肿瘤，在老年小鼠中发展髓系恶性肿瘤。在 T 细胞恶性肿瘤中，Notch1 及其下游效应物的过度表达导致了胸腺细胞成熟的加速。CD19-P53CKO 小鼠的脾脏中边缘区扩张，随后发展为边缘区淋巴瘤，其中一些进展为弥漫性大 B 细胞淋巴瘤。有趣的是，与野生型脾脏的边缘区或滤泡细胞相比，边缘区和弥漫性大 B 细胞淋巴瘤具有独特的基因表达特征，表现为 PI3K 通路的激活。本研究表明，由于独特的基因表达程序的启动，谱系特异性的 P53 缺失导致了不同的表型。
