Characterization of murine JAK2V617F-positive myeloproliferative disease
Characterization of murine JAK2V617F-positive myeloproliferative disease
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DOI：
10.1158/0008-5472.can-06-2210
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发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Deininger, Michael W. N.
中科院分区：
文献类型：
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作者：
Bumm, Thomas G. P.;Elsea, Collin;Deininger, Michael W. N.
JAK2(V617F) 突变存在于几乎所有真性红细胞增多症 (PV) 患者、大部分原发性血小板增多症和特发性骨髓纤维化患者中，在非典型骨髓增殖性疾病 (MPD) 中较少见。我们发现，将 JAK2(V617F) 转导的骨髓移植到 BALB/c 小鼠中会诱导类似于人类 PV 的 MPD，其特征为红细胞增多、粒细胞增多、髓外造血和骨髓纤维化，但不包括血小板增多。骨髓和脾脏的荧光激活细胞分选显示常见骨髓祖细胞、粒细胞-单核细胞和巨核细胞-红细胞祖细胞成比例扩增。巨核细胞和晚期红系祖细胞显着增加，而早期红系祖细胞仅适度扩增。促红细胞生成素 (Epo) 受体表达在早期成红细胞中减少，但在晚期成红细胞中正常。 Epo 和粒细胞集落刺激因子（但粒细胞巨噬细胞集落刺激因子）的血清水平降低，而肿瘤坏死因子-α 升高，可能对 JAK2（V617F）阴性造血产生负面影响。这些数据表明，JAK2(V617F) 小鼠的红细胞增多和粒细胞增多是细胞内在因素和外在因素之间复杂相互作用的最终结果。没有发生血栓栓塞事件，也没有动物死于该疾病，这表明人类疾病的表现有其他因素。该疾病不可移植，长期观察显示大多数 JAK2(V617F) 小鼠的血细胞计数正常化，表明该突变可能不会赋予自我更新能力。
The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.