Abstract LB-22: Establishment of a novel tumor-prone mouse model expressing human ETV7
Authors: Numata Masashi , Geltink Rmon Klein , Grosveld Gerard 
Published: May 2015

Abstract
ETS (E26-transformation specific) transcription factors are involved in diverse biological processes including cellular proliferation, survival, differentiation, development, and transformation. We originally identified the ETS transcription factor ETV7, which is highly homologous to ETV6/TEL, a frequent target of chromosomal translocation in human leukemia. Previously we have shown that ETV7 cooperates with Myc in B-cell lymphomagenesis and ectopic expression of ETV7 in mouse bone marrow (BM) causes a myeloproliferative disease with a long latency. This indicates that ETV7 is a hematopoietic oncoprotein requiring cooperating mutations to induce leukemic transformation. Recently we found that ETV7 expression is upregulated in approximately 70% of pediatric ALL or AML samples. This suggests a possible oncogenic function of ETV7 in a variety of human leukemia patients. However, the molecular mechanism of ETV7-associated leukemogenesis remains to be elucidated.
Mouse models that faithfully recapitulate human tumors are very valuable for the investigation of the oncogenic mechanism in vivo. Despite its high level of conservation among vertebrates, the ETV7 gene locus is deleted in part of the rodents including Mus musculus. To circumvent this limitation, we have generated an ETV7 BAC transgenic (ETV7 Tg) mouse that carries a single copy of a human BAC DNA containing the ETV7 gene locus. ETV7 heterozygous (ETV7 Tg+/WT) mice are fertile, born at Mendelian frequency, show normal development and are not tumor-prone. The ETV7 expression pattern in hematopoietic cells of ETV7 Tg+/WT mice was evaluated by qRT-PCR and was very similar to that of human cells. Based on flow cytometry analysis with antibodies specific for lymphoid, myeloid, and erythroid cell types, the cellularity and distribution of hematopoietic cells in ETV7 BM, spleen, and thymus are similar to those of WT mice. Meanwhile, ETV7 BM cells grew faster in culture compared to WT control, and ETV7 enhanced proliferation of myeloid cells in vitro. To examine the oncogenic function of ETV7 in vivo, we crossed ETV7 mice with oncogenic mouse models. ETV7 greatly accelerated PTEN deletion-evoked leukemogenesis in the PTENFL/FLMx1+/- ETV7 Tg+/WT mice. Moreover, ETV7 shortened the onset of tumor incidence in ARF-/- mice. Interestingly, a small number of ARF-/- ETV7 Tg+/WT mice succumbed to myeloid leukemia, indicating that ETV7 affects the tumor spectrum of ARF-/- mice. In this study we established a novel tumor-prone mouse model expressing human ETV7, which is a valuable experimental animal model to investigate the mechanism of ETV7-associated human tumorigenesis in vivo.
Citation Format: Masashi Numata, Rmon Klein Geltink, Gerard Grosveld. Establishment of a novel tumor-prone mouse model expressing human ETV7. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-22. doi:10.1158/1538-7445.AM2014-LB-22