de Oliveira Bruna Sabino Pinho, Giovinazzo Alessandro, Putti Sabrina, Merolle Matilde, Orsini Tiziana, Tocchini-Valentini Giuseppe D, Lancrin Christophe, Naro Fabio, Pellegrini Manuela
Institute of Biochemistry and Cell Biology (IBBC- CNR), Via Ercole Ramarini, 32 Monterotondo Scalo, 00015, Rome, Italy.
Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161, Rome, Italy.
Exp Hematol Oncol. 2024 Aug 6;13(1):81. doi: 10.1186/s40164-024-00544-0.
Ataxia-telangiectasia (A-T) is a rare autosomal recessive multi-system and life-shortening disease, characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition, with high incidence of leukemia and lymphoma. A-T is caused by mutations in the gene encoding for ATM protein that has a major role in maintaining the integrity of the genome. Because there are no cures for A-T, we aimed to tackle immunodeficiency and prevent cancer onset/progression by transplantation therapy.
Enriched hematopoietic stem/progenitor cells (HSPCs), collected from bone marrow of wild-type mice, were transplanted in the caudal vein of 1 month old conditioned Atm mice.
Genomic analyses showed that transplanted Atm positive cells were found in lymphoid organs. B cells isolated from spleen of transplanted mice were able to undergo class switching recombination. Thymocytes were capable to correctly differentiate and consequently an increase of helper T cells and TCRβ expressing cells was observed. Protein analysis of isolated T and B cells from transplanted mice, revealed that they expressed Atm and responded to DNA damage by initiating an Atm-dependent phosphorylation cascade. Indeed, aberrant metaphases were reduced in transplanted Atm-deficient mice. Six months after transplantation, Atm mice showed signs of aging, but they maintained the rescue of T cells maturation, showed DNA damage response, and prevented thymoma.
We can conclude that wild-type enriched HSPCs transplantation into young Atm-deficient mice can ameliorate A-T hematopoietic phenotypes and prevent tumor of hematopoietic origin.
共济失调毛细血管扩张症（A-T）是一种罕见的常染色体隐性多系统疾病，会缩短寿命，其特征为进行性小脑神经变性、免疫缺陷、辐射敏感性和癌症易感性，白血病和淋巴瘤发病率较高。A-T由编码ATM蛋白的基因突变引起，该蛋白在维持基因组完整性方面起主要作用。由于A-T无法治愈，我们旨在通过移植疗法解决免疫缺陷问题并预防癌症的发生/进展。
从野生型小鼠骨髓中收集的富集造血干/祖细胞（HSPCs）被移植到1月龄经条件处理的Atm小鼠的尾静脉中。
基因组分析表明，在淋巴器官中发现了移植的Atm阳性细胞。从移植小鼠脾脏中分离出的B细胞能够进行类别转换重组。胸腺细胞能够正确分化，因此观察到辅助性T细胞和表达TCRβ的细胞增加。对移植小鼠分离出的T细胞和B细胞进行蛋白质分析，结果显示它们表达Atm，并通过启动依赖于Atm的磷酸化级联反应对DNA损伤做出反应。实际上，移植的Atm缺陷小鼠中异常中期细胞减少。移植后6个月，Atm小鼠出现衰老迹象，但它们维持了T细胞成熟的挽救，表现出DNA损伤反应，并预防了胸腺瘤。
我们可以得出结论，将野生型富集的HSPCs移植到年轻的Atm缺陷小鼠中可以改善A-T造血表型并预防造血源性肿瘤。
