Aberrant expression of the Evi1 (ecotropic virus integration site 1) proto-oncogene has been associated with hematopoietic malignancies in both mice and man. To determine the effect of enforced expression of Evi1 in vivo, we developed a transgenic mouse model utilizing the murine Sca-1 (Ly-6E.1) promoter. Here, we describe the generation and analysis of three independent lines of Evi1 transgenic mice. Transgenic animals of two founder lines developed normally. These mice did not show any obvious hematological abnormalities but showed a significant reduction in the number of bone marrow colony-forming unit erythroid (CFU-E)-derived colonies. This implies a defect of normal erythroid hematopoiesis affecting relatively late erythroid progenitor cells. We also show that when newborn Evi1 transgenic mice of these two lines were infected with Cas-Br-M MuLV, tumor incidence was greatly enhanced in comparison with nontransgenic littermates, indicating an increased susceptibility for leukemia development. Interestingly, analysis of a third founder line revealed that all male progeny consistently displayed severely impaired erythropoiesis with major defects in the bone marrow, spleen and peripheral blood. Taken together, our results present the first evidence of Evi1 disturbing normal erythropoiesis in vivo and provides evidence for cooperative potential of Evi1 in tumor progression. Leukemia (2000) 14, 1876-1884.
Background: Sp4 is a zinc finger transcription factor which is closely related to Sp1 and Sp3. All three proteins recognize the same DNA elements and can act as transcriptional activators through glutaminerich activation domains. Unlike Sp1 and Sp3, which are ubiquitous proteins, Sp4 is highly abundant in the central nervous system, but also detectable in many other tissues.
Background: EBV þ LMS is a rare cancer that develops in patients with immune deficiency. EBV þ LMS responds poorly to radiation and chemotherapy resulting in limited treatment options and poor outcomes.1 Tabelecleucel is an investigational, off-theshelf, genetically unmodified, allogeneic T-cell immunotherapy targeting EBV antigens.Here we report the efficacy and safety of tabelecleucel in a subgroup of EBV þ LMS patients from 3 clinical trials. Methods: Tabelecleucel was evaluated in 2 single-center, open-label studies (NCT00002663 [Study 1], NCT01498484 [Study 2]) and a multi-center expanded access protocol (NCT02822495 [Study 3]). Tabelecleucel was given at 1.0-2.0 x 10 6 cells/kg/dose on days 1, 8, and 15 of every 4-6-week cycle, and imaging was performed before the 1 st dose of each cycle. Results: A total of 12 patients with EBV þ LMS received 1 dose of tabelecleucel, 10 of whom were assessed for responses (1 patient was not evaluable and 1 patient was too early to assess). Using CT-based RECIST 1.1 criteria, 2 patients achieved a partial response (objective response rate ¼ 17%) and 8 patients achieved stable disease. In studies 1 and 2 where longer follow-up is available, 6 of 8 patients survived 27 months. The median survival (95% CI) is 77.4 (18, NE) months. At the time of this analysis, metabolic responses were available in study 3: 3 of the 4 patients (75%) achieved a metabolic response. The safety profile is consistent with previously reported data; 2 no new safety signals have been identified. Conclusions: This analysis represents one of the larger prospective studies of patients with EBV þ LMS. The combination of CT-based and metabolic responses to tabelecleucel, in the context of prolonged survival, demonstrate that tabelecleucel (also known as tab-cel TM ) may provide clinical benefit in this typically radiation-and chemotherapyresistant disease. Tabelecleucel is well tolerated in this population of patients.
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