MEMBRANE-ASSOCIATED CD19-LYN COMPLEX IS AN ENDOGENOUS P53-INDEPENDENT AND BCL-2-INDEPENDENT REGULATOR OF APOPTOSIS IN HUMAN B-LINEAGE LYMPHOMA-CELLS

作者：MYERS DE; JUN X; WAD**** KG; FORSYTH C; CHELSTROM LM; GUNTHER RL; TUMER NE; BOLEN J; UCKUN FM

来源：Proceedings of the National Academy of Sciences of the United States of America, 1995, 92(21): 9575-9579.

DOI：10.1073/pnas.92.21.9575

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.

• 出版日期1995-10-10