Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bcl-2-independent regulator of apoptosis in human B-lineage lymphoma cells

Dorothea E. Myers, Xiao Jun, Kevin G. Waddick, Craig Forsyth, Lisa M. Chelstrom, Roland L. Günther, Nilgun E. Tumer, Joseph Bolen, Fatih M. Uckun

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9575-9579
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number21
DOIs
StatePublished - Oct 10 1995

All Science Journal Classification (ASJC) codes

  • General

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