Apoptosis and macrophage-mediated deletion of precursor B cells in the bone marrow of E mu-myc transgenic mice.
Transgenic mice expressing the c-myc proto-oncogene under the control of the Ig heavy chain enhancer (E mu-myc) all eventually develop clonal pre-B- or B-cell tumors. The preneoplastic period is characterized by increased polyclonal proliferation of pro-B and pre-B cells in the bone marrow (BM) associated with a reduced number of B cells, suggesting a high degree of B-cell loss. To examine the mechanisms of this cell loss, we have identified B220+ B-lineage cells within the BM of pretumorous E mu-myc transgenic mice by in vivo radiolabeling and electron microscope radioautography. Large mitotic B220(+)-labeled cells form prominent clusters in the extravascular compartment of the BM. Some B220+ small lymphocytes, as well as large lymphoid cells, enter BM sinusoids. However, in addition, large numbers of B220+ cells exhibit nuclear chromatin condensation, fragmentation, and other morphologic features characteristic of apoptotic cell death. Propidium iodide staining and flow cytometry of BM cells from pretumorous E mu-myc transgenic mice, as well as agarose gel electrophoresis of DNA, confirm extensive apoptosis. Many B220+ apoptotic cells are closely associated with the extensive processes of prominent macrophages that contain numerous B220+ apoptotic bodies and complex lysosomal systems. These results suggest that the constitutive expression of c-myc oncogene in BM B-lineage cells, which increases the proliferation of precursor B cells, also leads to increased apoptotic cell death and rapid elimination by resident macrophages. Further mutations may be needed to block these protective mechanisms and permit surviving c-myc-dysregulated cells to leave the BM and to initiate tumorigenesis.
Jacobsen
K A
KA
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Prasad
V S
VS
Sidman
C L
CL
Osmond
D G
DG
D000818:Animals; D017209:Apoptosis; D001345:Autoradiography; D001402:B-Lymphocytes / Q000502:physiology* / Q000648:ultrastructure; D001854:Bone Marrow Cells; D004742:Enhancer Elements, Genetic; D005260:Female; D005434:Flow Cytometry; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000502:physiology* / Q000648:ultrastructure; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011419:Propidium; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology; D013194:Staining and Labeling
D007143:Immunoglobulin Heavy Chains; D016271:Proto-Oncogene Proteins c-myc; D011419:Propidium