Mullenders Jasper, Aranda-Orgilles Beatriz, Lhoumaud Priscillia, Keller Matthew, Pae Juhee, Wang Kun, Kayembe Clarisse, Rocha Pedro P, Raviram Ramya, Gong Yixiao, Premsrirut Prem K, Tsirigos Aristotelis, Bonneau Richard, Skok Jane A, Cimmino Luisa, Hoehn Daniela, Aifantis Iannis
Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016 Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
Howard Hughes Medical Institute, Department of Pathology, and Center for Health Informatics and Bioinformatics, School of Medicine and Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10016.
J Exp Med. 2015 Oct 19;212(11):1833-50. doi: 10.1084/jem.20151323. Epub 2015 Oct 5.
The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.
黏连蛋白复合体（由Rad21、Smc1a、Smc3和Stag2蛋白组成）对于有丝分裂过程中姐妹染色单体的正确分离至关重要。最近在包括急性髓系白血病（AML）在内的多种人类恶性肿瘤中发现了黏连蛋白复合体的突变。为了在体内研究黏连蛋白潜在的肿瘤抑制功能，我们构建了一系列shRNA小鼠模型，其中内源性黏连蛋白可以被诱导沉默。值得注意的是，沉默黏连蛋白复合体成员对细胞活力没有有害影响。此外，敲低黏连蛋白导致小鼠造血祖细胞的再接种能力增强。然而，体内黏连蛋白沉默迅速改变了干细胞稳态和骨髓生成。同样，我们发现参与髓单核细胞成熟和分化的基因的染色质可及性和表达发生了广泛变化。最后，老年黏连蛋白敲低小鼠出现了与骨髓增殖性疾病/肿瘤（MPN）非常相似的临床表现，包括不同程度的髓外造血（髓样化生）和脾肿大。我们的结果首次成功证明了黏连蛋白复合体具有肿瘤抑制功能，同时也证实黏连蛋白突变是白血病发生过程中的早期事件，促进了髓系恶性肿瘤的潜在发展。
