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Fatal Acute Lymphoblastic Leukemia in Mice Transgenic for B Cell-Restricted bcl-x_L and c-myc¹

Penelope J. Swanson^*, Sheri L. Kuslak, Wei Fang^*, Lina Tze^*, Patrick Gaffney^*, Scott Selby^*, Keli L. Hippen^*, Gabriel Nunez, Charles L. Sidman and Timothy W. Behrens^2,*

^* Department of Medicine, Cancer Center, and Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Pathology, University of Michigan, Ann Arbor, MI 48109; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267

Expression of the c-myc gene is frequently dysregulated in malignant tumors and translocations of c-myc into the Ig H chain locus are associated with Burkitt’s-type lymphoma. There is indirect evidence that bcl-x, an anti-apoptotic member of the bcl-2 gene family, may also contribute to a variety of B lymphoid tumors. In this study, we show that mice transgenic for both B cell-restricted c-myc and bcl-x_L developed aggressive, acute leukemias expressing early B lineage and stem cell surface markers. Of interest, the tumor cells proliferated and differentiated down the B cell developmental pathway following in vitro treatment with IL-7. Analysis of sorted leukemic cells from spleen indicated constitutive expression of sterile µ and transcripts in combination with evidence for D-J_H DNA rearrangements. Several B cell-specific genes were either not expressed or were expressed at low levels in primary tumor cells and were induced following culture with IL-7. IL-7 also increased V-J and V-DJ_H rearrangements. These data demonstrate oncogenic synergy between c-myc and bcl-x_L in a new mouse model for acute lymphoblastic leukemia. Tumors in these animals target an early stage in B cell development characterized by the expression of both B lineage and stem cell genes.

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