Regulation of the apoptotic response to radiation damage in B cell development.
B lymphocyte precursor cells are ultrasensitive to DNA damage induced by irradiation and drugs and die by apoptosis at very low levels of exposure. Previous studies have shown that this high level sensitivity is p53-dependent, associated with very low level expression of Bcl-2 protein and can be reversed by expression of a bcl-2 transgene. We show here that transition from the pro-B to pre-B and then mature B cell stages of murine lymphopoiesis is accompanied by changes in proliferating cells in sensitivity to X-irradiation induced apoptosis and that this is paralleled by variation in the ratio of anti-(Bcl-2/Bcl-chiL) to pro-(Bax) apoptotic proteins. These are however not fixed or invariant features of developmental stage as they can be modulated by interactions via adhesive interactions with stromal cells, stromal proteins and growth factors. We interpret these data in the context of the stringent developmental regulation of clonal lymphopoiesis and the contingency programming of cells that have extensive proliferative potential with a very low threshold for apoptosis following DNA damage.
Nishii
K
K
Leukaemia Research Fund Centre at the Institute of Cancer Research, London.
Gibbons
D L
DL
Titley
I
I
Papworth
D
D
Goodhead
D T
DT
Greaves
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology*; D018960:Hyaluronan Receptors / Q000032:analysis; D006820:Hyaluronic Acid / Q000494:pharmacology; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D018960:Hyaluronan Receptors; D015851:Interleukin-7; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D006820:Hyaluronic Acid