Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-xL and c-myc.
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 micro and kappa 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-Jkappa 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.
Swanson
Penelope J
PJ
Department of Medicine, Cancer Center, and Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Kuslak
Sheri L
SL
Fang
Wei
W
Tze
Lina
L
Gaffney
Patrick
P
Selby
Scott
S
Hippen
Keli L
KL
Nunez
Gabriel
G
Sidman
Charles L
CL
Behrens
Timothy W
TW
D000818:Animals; D002478:Cells, Cultured; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D016259:Genes, myc / Q000502:physiology*; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein