Induction of histiocytic sarcoma in mouse skeletal muscle.
Induction of histiocytic sarcoma in mouse skeletal muscle.
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DOI：
10.1371/journal.pone.0044044
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wagers AJ
中科院分区：
文献类型：
--
作者：
Liu J;Hettmer S;Milsom MD;Hofmann I;Hua F;Miller C;Bronson RT;Wagers AJ
髓样肉瘤是未成熟髓样细胞的髓外积聚，其可存在或不存在骨髓或外周血病理受累的证据，并且通常与急性髓性白血病（AML）的诊断一致或先于急性髓性白血病（AML）的诊断。实验模型的缺乏阻碍了骨髓肉瘤的研究，并导致我们建立了一个新的系统，其中肿瘤诱导可以在一个容易获得的非造血组织室进行评估。使用致癌Kras（G12 V）到p16/p19−/−骨髓细胞的体外转导，我们产生了可移植的白血病起始细胞，这些细胞在免疫功能低下的NOD.SCID小鼠的骨骼肌中迅速诱导肿瘤形成。在该模型中，小鼠组织细胞肉瘤（相当于人骨髓肉瘤）在细胞植入后30-50天出现在注射部位，由紧密堆积的单型细胞组成，这些细胞为CD 48+、CD 47+和Mac 1+，其他造血谱系标志物表达较低或不表达。肿瘤细胞还浸润骨髓、脾脏和其他非造血器官的肿瘤荷瘤动物，导致系统性疾病（白血病）在两个星期内的肿瘤检测。P16/p19−/−; Kras（G12 V）髓样肉瘤是多克隆的，在二次移植过程中选择了优势克隆。组织细胞肉瘤荷瘤小鼠表现出的系统性白血病表型与通过静脉移植相同供体细胞引入白血病的动物几乎相同。肌肉注射MLL-AF 9白血病细胞也能诱导小鼠组织细胞肉瘤。本研究建立了一种新的，可移植的小鼠组织细胞/髓样肉瘤模型，概括了这些恶性肿瘤的自然进展，全身性疾病，并表明细胞自主白血病发生机制。
Myeloid sarcomas are extramedullary accumulations of immature myeloid cells that may present with or without evidence of pathologic involvement of the bone marrow or peripheral blood, and often coincide with or precede a diagnosis of acute myeloid leukemia (AML). A dearth of experimental models has hampered the study of myeloid sarcomas and led us to establish a new system in which tumor induction can be evaluated in an easily accessible non-hematopoietic tissue compartment. Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19−/− bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice. In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30–50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers. Tumor cells also infiltrated the bone marrow, spleen and other non-hematopoietic organs of tumor-bearing animals, leading to systemic illness (leukemia) within two weeks of tumor detection. P16/p19−/−; Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation. The systemic leukemic phenotypes exhibited by histiocytic sarcoma-bearing mice were nearly identical to those of animals in which leukemia was introduced by intravenous transplantation of the same donor cells. Moreover, murine histiocytic sarcoma could be similarly induced by intramuscular injection of MLL-AF9 leukemia cells. This study establishes a novel, transplantable model of murine histiocytic/myeloid sarcoma that recapitulates the natural progression of these malignancies to systemic disease and indicates a cell autonomous leukemogenic mechanism.
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影响因子：
46.9
作者：
Dai, SM;Chen, HH;Flanagan, SD
通讯作者：
Flanagan, SD
DOI：
10.1073/pnas.0906549106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Chan, Keith Syson;Espinosa, Inigo;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
2.2
作者：
Bonnefoix, T;Bonnefoix, P;Sotto, JJ
通讯作者：
Sotto, JJ
影响因子：
3.2
作者：
Johnston, Donna L.;Alonzo, Todd A.;Woods, William G.
通讯作者：
Woods, William G.
影响因子：
50.3
作者：
Carrasco, Daniel R.;Fenton, Tim;DePinho, Ronald A.
通讯作者：
DePinho, Ronald A.