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Transmembrane protein 207 (TMEM207) is an important molecule involved in invasiveness of gastric signet ring cell carcinoma. To understand the pathobiological effects of TMEM207, we generated thirteen transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), where mouse TMEM207 is expressed heterotrophically, regulated by the proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). A C57BL/6-Tg (ITF-TMEM207) mouse line unexpectedly exhibited a high incidence of a spontaneous condition resembling myeloproliferative disease-like phenotype. Increased numbers of CD117+ cells and appearance of dysplastic myeloid cells in bone marrow were observed. These histopathological features suggested human myeloproliferative disease or its precursor manifestations, and were found in almost all mice within 1 year. TMEM207 immunoreactivity was identified in megakaryocytes and erythroblasts of the transgenic mice. The ITF-TMEM207 construct was inserted into Atg4b on murine chromosome 1. Myeloproliferative disease was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. However, although several other genetically manipulated animal models of myeloproliferative disease and Atg4b knockout mice exist, this mouse line harboring a mutated Atg4b gene, and with overexpression of TMEM207 protein, has not been reported as a model of myeloproliferative disease to date. The present study demonstrated that the C57BL/6-Tg (ITF-TMEM207) mouse may be a valuable model for improved understanding of human myeloproliferative disease., Summary: We generated a mouse model similar to human myeloproliferative disease-like phenotype. Mutations in Atg4b and overexpression of TMEM207 may lead to myeloproliferative disease in the present model.

TMEM207 was first characterized as being an important molecule for the invasion activity of gastric signet-ring cell carcinoma cells. In order to unravel the pathological properties of TMEM207, we generated several transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), in which murine TMEM207 was ectopically expressed under a truncated (by ~200 bp) proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). Unexpectedly, a C57BL/6-Tg (ITF-TMEM207) mouse line exhibited a high incidence of spontaneous intradermal tumors with histopathological features that resembled those of various human cutaneous adnexal tumors. These tumors were found in ~14% female and 13% of male 6- to 12-month-old mice. TMEM207 immunoreactivity was found in hair follicle bulge cells in non-tumorous skin, as well as in cutaneous adnexal tumors of the transgenic mouse. The ITF-TMEM207 construct in this line appeared to be inserted to a major satellite repeat sequence at chromosome 2, in which no definite coding molecule was found. In addition, we also observed cutaneous adnexal tumors in three other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. We believe that the C57BL/6-Tg (ITF-TMEM207) mouse might be a useful model to understand human cutaneous adnexal tumors.