Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells.
CD19 receptor is expressed at high levels on human B-lineage lymphoid cells and is physically associated with the Src protooncogene family protein-tyrosine kinase Lyn. Recent studies indicate that the membrane-associated CD19-Lyn receptor-enzyme complex plays a pivotal role for survival and clonogenicity of immature B-cell precursors from acute lymphoblastic leukemia patients, but its significance for mature B-lineage lymphoid cells (e.g., B-lineage lymphoma cells) is unknown. CD19-associated Lyn kinase can be selectively targeted and inhibited with B43-Gen, a CD19 receptor-specific immunoconjugate containing the naturally occurring protein-tyrosine kinase inhibitor genistein (Gen). We now present experimental evidence that targeting the membrane-associated CD19-Lyn complex in vitro with B43-Gen triggers rapid apoptotic cell death in highly radiation-resistant p53-Bax- Ramos-BT B-lineage lymphoma cells expressing high levels of Bcl-2 protein without affecting the Bcl-2 expression level. The therapeutic potential of this membrane-directed apoptosis induction strategy was examined in a scid mouse xenograft model of radiation-resistant high-grade human B-lineage lymphoma. Remarkably, in vivo treatment of scid mice challenged with an invariably fatal number of Ramos-BT cells with B43-Gen at a dose level < 1/10 the maximum tolerated dose resulted in 70% long-term event-free survival. Taken together, these results provide unprecedented evidence that the membrane-associated anti-apoptotic CD19-Lyn complex may be at least as important as Bcl-2/Bax ratio for survival of lymphoma cells.
Myers
D E
DE
Biotherapy Program, University of Minnesota Health Sciences Center, Minneapolis 55455, USA.
Jun
X
X
Waddick
K G
KG
Forsyth
C
C
Chelstrom
L M
LM
Gunther
R L
RL
Tumer
N E
NE
Bolen
J
J
Uckun
F M
FM
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D019833:Genistein; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D000922:Immunotoxins / Q000627:therapeutic use; D007529:Isoflavones / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019061:src-Family Kinases / Q000378:metabolism*
D018941:Antigens, CD19; D004791:Enzyme Inhibitors; D018796:Immunoconjugates; D000922:Immunotoxins; D007529:Isoflavones; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases