Nakamura Yuka, Ichikawa Motoshi, Oda Hideaki, Yamazaki Ieharu, Sasaki Ko, Mitani Kinuko
Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Department of Pathology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
Leuk Res. 2018 Nov;74:14-20. doi: 10.1016/j.leukres.2018.09.015. Epub 2018 Sep 26.
The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1-expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells.
由t(3;21)易位产生的RUNX1-EVI1基因编码一种嵌合转录因子，是原发性急性巨核细胞白血病发生以及造血干细胞肿瘤白血病转化中的致病基因。杂合性RUNX1-EVI1基因敲入小鼠因中枢神经系统和脊髓出血以及胎儿肝脏中确定性造血完全消失而在子宫内死亡。另一方面，嵌合基因敲入小鼠会发生急性巨核细胞白血病。我们通过移植逆转录病毒感染的骨髓细胞创建了另一种RUNX1-EVI1小鼠模型。一些移植了表达RUNX1-EVI1骨髓细胞的小鼠在八个月内发生了急性巨核细胞白血病，其他非白血病小鼠在大约一岁时出现血小板增多症。在非白血病小鼠中，发育异常的巨核细胞在骨髓中增殖，并经常浸润到脾脏，这与骨髓纤维化无关。在白血病小鼠中，它们的肿瘤细胞c-kit和CD41呈阳性，TER119呈阴性。尽管在电子显微镜分析中它们的血小板过氧化物酶呈阴性，但它们的细胞质中有多个中心粒，这是经历核内有丝分裂的巨核细胞的特征。白血病细胞可连续移植，使用定量RT-PCR阵列进行的基因表达分析显示，与正常骨髓细胞相比，它们的干细胞、原始造血细胞和内皮细胞相关基因的表达显著升高。所有这些数据表明，RUNX1-EVI1导致巨核细胞系发育异常造血或白血病，并赋予了未成熟造血细胞独特的基因表达谱。
