EVI1 induces myelodysplastic syndrome in mice
Silvia Buonamici, … , Yogen Saunthararajah, Giuseppina Nucifora
Silvia Buonamici, … , Yogen Saunthararajah, Giuseppina Nucifora
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):713-719. https://doi.org/10.1172/JCI21716.
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Article Hematology

EVI1 induces myelodysplastic syndrome in mice

Abstract

Myelodysplasia is a hematological disease in which genomic abnormalities accumulate in a hematopoietic stem cell leading to severe pancytopenia, multilineage differentiation impairment, and bone marrow (BM) apoptosis. Mortality in the disease results from pancytopenia or transformation to acute myeloid leukemia. There are frequent cytogenetic abnormalities, including deletions of chromosomes 5, 7, or both. Recurring chromosomal translocations in myelodysplasia are rare, but the most frequent are the t(3;3)(q21;q26) and the inv(3)(q21q26), which lead to the inappropriate activation of the EVI1 gene located at 3q26. To better understand the role of EVI1 in this disease, we have generated a murine model of EVI1-positive myelodysplasia by BM infection and transplantation. We find that EVI1 induces a fatal disease of several stages that is characterized by severe pancytopenia. The disease does not progress to acute myeloid leukemia. Comparison of in vitro and in vivo results suggests that EVI1 acts at two levels. The immediate effects of EVI1 are hyperproliferation of BM cells and downregulation of EpoR and c-Mpl, which are important for terminal erythroid differentiation and platelet formation. These defects are not fatal, and the mice survive for about 10 months with compensated hematopoiesis. Over this time, compensation fails, and the mice succumb to fatal peripheral cytopenia.

Authors

Silvia Buonamici, Donglan Li, Yiqing Chi, Rui Zhao, Xuerong Wang, Larry Brace, Hongyu Ni, Yogen Saunthararajah, Giuseppina Nucifora

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Figure 1

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EVI1 causes a fatal disease in reconstituted mice. (A) Retroviral DNA co...
EVI1 causes a fatal disease in reconstituted mice. (A) Retroviral DNA constructs used in Phoenix cell line. The 5′ long terminal repeat (LTR) provides the promoter for a transcript that includes EVI1 and a gene encoding resistance to G418 (NeoR, indicated by the arrow). Internal ribosome entry site (IRES) is required for the translation of the NeoR transcript. HIII is the unique HindIII restriction site present in the EVI1 cDNA. The location of the probe used for Southern blot analysis is indicated. HA, hemagglutinin epitope. (B) Western blot analysis of EVI1-producing packaging Phoenix cells (lane 1), vector-producing packaging Phoenix cells (lane 2), control mouse BM cells (lane 3), and EVI1-positive BM cells (lanes 4 and 5) confirms the appropriate expression of EVI1 only in EVI1-positive samples (lanes 1, 4, and 5). (C) Southern blot analysis of BM cells from reconstituted EVI1-positive mice (lanes 4 and 5) and control mice (lane 3). (D) Counts of wbc’s (diamonds, × 103/μl), rbc’s (squares, × 106/μl), platelets (horizontal bars, × 105/μl), and levels of hemoglobin (crosses, g/dl) in PB of EVI1-positive mice (left) and in control mice (right). (E) The solid line shows the Kaplan-Meier survival curve of EVI1-positive reconstituted mice. All EVI1-positive mice died or were killed because of disease conditions. The dashed line represents the survival of the control mice.