Fatal Acute Lymphoblastic Leukemia in Mice Transgenic for B Cell-Restricted bcl-x_L and c-myc~1

摘要

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 mu and k 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-JK and V-DJ_H rearrangements.These data demonstrate oncogenic synergy between c-myc and bcl-xL 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.