Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-XL and c-myc

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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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-xL 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 κ transcripts in combination with evidence for D-JH 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-Jκ and V-DJH rearrangements. These data demonstrate oncogenic synergy between c-myc and bcl-xL in a new mouse model for acute lymphobiastic 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.

Original languageEnglish (US)
Pages (from-to)6684-6691
Number of pages8
JournalJournal of Immunology
Volume172
Issue number11
DOIs
StatePublished - Jun 1 2004

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