Lacout Catherine, Pisani Didier F, Tulliez Micheline, Gachelin Françoise Moreau, Vainchenker William, Villeval Jean-Luc
Institut National de la Sante et de la Recherche Medicale (INSERM) U790, Université Paris XI, Institut Gustave Roussy (IGR), Villejuif, France.
Blood. 2006 Sep 1;108(5):1652-60. doi: 10.1182/blood-2006-02-002030. Epub 2006 May 2.
A JAK2(V617F) mutation is frequently found in several BCR/ABL-negative myeloproliferative disorders. To address the contribution of this mutant to the pathogenesis of these different myeloproliferative disorders, we used an adoptive transfer of marrow cells transduced with a retrovirus expressing JAK2(V617F) in recipient irradiated mice. Hosts were analyzed during the 6 months after transplantation. For a period of 3 months, mice developed polycythemia, macrocytosis and usually peripheral blood granulocytosis. Transient thrombocytosis was only observed in a low-expresser group. All mice displayed trilineage hyperplasia in marrow and spleen along with an amplification of myeloid and erythroid progenitor cells and a formation of endogenous erythroid colonies. After 3 to 4 months, polycythemia regressed, abnormally shaped red blood cells and platelets were seen in circulation, and a deposition of reticulin fibers was observed in marrow and spleen. Development of fibrosis was associated with anemia, thrombocytopenia, high neutrophilia, and massive splenomegaly. These features mimic human polycythemia vera and its evolution toward myelofibrosis. This work demonstrates that JAK2(V617F) is sufficient for polycythemia and fibrosis development and offers an in vivo model to assess novel therapeutic approaches for JAK2(V617F)-positive pathologies. Questions remain regarding the exact contribution of JAK2(V617F) in other myeloproliferative disorders.
JAK2（V617F）突变在几种BCR/ABL阴性骨髓增殖性疾病中经常被发现。为了探究这种突变体在这些不同骨髓增殖性疾病发病机制中的作用，我们在受辐照的受体小鼠中采用了过继转移经表达JAK2（V617F）的逆转录病毒转导的骨髓细胞的方法。在移植后的6个月内对宿主进行分析。在3个月的时间里，小鼠出现了红细胞增多症、大红细胞症，并且通常伴有外周血粒细胞增多。短暂的血小板增多症仅在低表达组中观察到。所有小鼠的骨髓和脾脏均出现三系增生，同时伴有髓系和红系祖细胞的扩增以及内源性红系集落的形成。3至4个月后，红细胞增多症消退，循环中出现异形红细胞和血小板，并且在骨髓和脾脏中观察到网状纤维沉积。纤维化的发展与贫血、血小板减少、高嗜中性粒细胞增多以及巨大脾肿大有关。这些特征模拟了人类真性红细胞增多症及其向骨髓纤维化的演变。这项工作表明JAK2（V617F）足以导致红细胞增多症和纤维化的发展，并提供了一个体内模型来评估针对JAK2（V617F）阳性疾病的新型治疗方法。关于JAK2（V617F）在其他骨髓增殖性疾病中的确切作用仍存在疑问。
