A murine model of acute myeloid leukemia with Evi1 overexpression and autocrine stimulation by an intracellular form of GM-CSF in DA-3 cells

Abstract

The poor treatment response of acute myeloid leukemia (AML) overexpressing high-risk oncogenes such as EVI1, demands specific animal models for new treatment evaluations. Evi1 is a common site of activating integrations in murine leukemia virus (MLV)-induced AML and in retroviral and lentiviral gene-modified HCS. Still, a model of overt AML induced by Evi1 has not been generated. Cell lines from MLV-induced AML are growth factor-dependent and non-transplantable. Hence, for the leukemia maintenance in the infected animals, a growth factor source such as chronic immune response has been suggested. We have investigated whether these leukemias are transplantable if provided with growth factors. We show that the Evi1⁺DA-3 cells modified to express an intracellular form of GM-CSF, acquired growth factor independence and transplantability and caused an overt leukemia in syngeneic hosts, without increasing serum GM-CSF levels. We propose this as a general approach for modeling different forms of high-risk human AML using similar cell lines.

Keywords::

• AML
• DA-3 cells
• EVI1
• GM-CSF
• intracellular cytokines
• Moloney murine leukemia virus

Acknowledgements

The authors are grateful to Asa-Lena Dackland for all help with FACS sorting and to Anna-Karin Person and Margareta Hagelin for excellent technical assistance at the animal facility. We are indebted to Professor Tore Midtvedt and Dr Fabio Sanchez for critical reading of the manuscript. This study was supported by the “Departamento Administrativo de Ciencia, Tecnologia e Innovacion, Colciencias” Colombia (contract 1102-4082-0538), Universidad Industrial de Santander, Colombia, the Swedish Research Council, the Swedish Cancer Foundation and Karolinska Institutet, Stockholm, Sweden.

Potential conflict of interest

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