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AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency

Maike Schwieger¹, Jürgen Löhler², Jutta Friel¹, Marina Scheller³, Ivan Horak³ and Carol Stocking¹

¹ Department of Cell and Virus Genetics, Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, D-20251 Hamburg, Germany
² Molecular Pathology Group, Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, D-20251 Hamburg, Germany
³ Department of Molecular Genetics, Institute of Molecular Pharmacology, Freie Universität Berlin, D-12207 Berlin, Germany

Address correspondence to Carol Stocking, Heinrich-Pette-Institut, Martinistrasse 52, D-20251 Hamburg, Germany. Phone: 49-40-480 51 273; Fax: 49-40-480 51 187; E-mail: stocking{at}hpi.uni-hamburg.de

The translocation (8;21), generating the AML1-ETO fusion protein, is one of the most frequent chromosomal abnormalities associated with acute myelogenous leukemia (AML). To elucidate its role in oncogenesis, bone marrow (BM) cells were infected with a retroviral vector carrying AML1-ETO and transplanted into mice. In contrast to previous transgenic mouse models, we show that AML1-ETO directly stimulates granulopoiesis, suppresses erythropoiesis, and impairs the maturation of myeloid, B, and T lymphoid cells in vivo. To determine the significance of earlier findings that expression of the tumor suppressor ICSBP is often downregulated in AML myeloblasts, AML1-ETO was introduced into BM cells derived from mice lacking the interferon regulatory factor ICSBP. Our findings demonstrate that AML1-ETO synergizes with an ICSBP deficiency to induce myeloblastic transformation in the BM, reminiscent of AML.

Key Words: leukemia • translocation (genetics) • IFN regulatory factor • B cell differentiation • myeloid differentiation

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