Moskow J J, Bullrich F, Huebner K, Daar I O, Buchberg A M
Jefferson Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Mol Cell Biol. 1995 Oct;15(10):5434-43. doi: 10.1128/MCB.15.10.5434.
Leukemia results from the accumulation of multiple genetic alterations that disrupt the control mechanisms of normal growth and differentiation. The use of inbred mouse strains that develop leukemia has greatly facilitated the identification of genes that contribute to the neoplastic transformation of hematopoietic cells. BXH-2 mice develop myeloid leukemia as a result of the expression of an ecotropic murine leukemia virus that acts as an insertional mutagen to alter the expression of cellular proto-oncogenes. We report the isolation of a new locus, Meis1, that serves as a site of viral integration in 15% of the tumors arising in BXH-2 mice. Meis1 was mapped to a distinct location on proximal mouse chromosome 11, suggesting that it represents a novel locus. Analysis of somatic cell hybrids segregating human chromosomes allowed localization of MEIS1 to human chromosome 2p23-p12, in a region known to contain translocations found in human leukemias. Northern (RNA) blot analysis demonstrated that a Meis1 probe detected a 3.8-kb mRNA present in all BXH-2 tumors, whereas tumors containing integrations at the Meis1 locus expressed an additional truncated transcript. A Meis1 cDNA clone that encoded a novel member of the homeobox gene family was identified. The homeodomain of Meis1 is most closely related to those of the PBX/exd family of homeobox protein-encoding genes, suggesting that Meis1 functions in a similar fashion by cooperative binding to a distinct subset of HOX proteins. Collectively, these results indicate that altered expression of the homeobox gene Meis1 may be one of the events that lead to tumor formation in BXH-2 mice.
白血病源于多种基因改变的积累，这些改变破坏了正常生长和分化的控制机制。使用会患白血病的近交系小鼠品系极大地促进了对有助于造血细胞肿瘤转化的基因的鉴定。BXH - 2小鼠由于嗜亲性鼠白血病病毒的表达而发生髓系白血病，该病毒作为插入诱变剂改变细胞原癌基因的表达。我们报告分离出一个新的基因座Meis1，它是BXH - 2小鼠中15%的肿瘤中病毒整合的位点。Meis1被定位到小鼠近端11号染色体上的一个独特位置，表明它代表一个新的基因座。对分离人类染色体的体细胞杂种进行分析，将MEIS1定位到人类2号染色体的2p23 - p12区域，该区域已知包含在人类白血病中发现的易位。Northern（RNA）印迹分析表明，Meis1探针检测到所有BXH - 2肿瘤中都存在一种3.8 kb的mRNA，而在Meis1基因座处有整合的肿瘤表达一种额外的截短转录本。鉴定出一个编码同源框基因家族新成员的Meis1 cDNA克隆。Meis1的同源结构域与同源框蛋白编码基因的PBX/exd家族的同源结构域关系最为密切，这表明Meis1通过与HOX蛋白的一个独特亚群协同结合以类似方式发挥作用。总的来说，这些结果表明同源框基因Meis1表达的改变可能是导致BXH - 2小鼠肿瘤形成的事件之一。
