A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice |
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Authors: | Kara J Johnson Ian J Griswold Thomas O'Hare Amie S Corbin Marc Loriaux Michael W Deininger Brian J Druker |
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Institution: | 1. Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, United States of America.; 2. Department of Pathology, Oregon Health & Science University, Portland, Oregon, United States of America.; 3. Howard Hughes Medical Institute, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, United States of America.;University of Kansas Medical Center, United States of America |
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Abstract: | The BCR-ABL tyrosine kinase is the defining feature of chronic myeloid leukemia (CML) and its kinase activity is required for induction of this disease. Current thinking holds that BCR-ABL forms a multi-protein complex that incorporates several substrates and adaptor proteins and is stabilized by multiple direct and indirect interactions. Signaling output from this highly redundant network leads to cellular transformation. Proteins known to be associated with BCR-ABL in this complex include: GRB2, c-CBL, p62DOK, and CRKL. These proteins in turn, link BCR-ABL to various signaling pathways indicated in cellular transformation. In this study we show that a triple mutant of BCR-ABL with mutations of the direct binding sites for GRB2, CBL, p62DOK and CRKL, is defective for transformation of primary hematopoietic cells in vitro and in a murine CML model, while it retains the capacity to induce IL-3 independence in 32D cells. Compared to BCR-ABL, the triple mutant''s ability to activate the MAP kinase and PI3-kinase pathways is severely compromised, while STAT5 phosphorylation is maintained, suggesting that the former are crucial for the transformation of primary cells, but dispensable for transformation of factor dependent cell lines. Our data suggest that inhibition of BCR-ABL-induced leukemia by disrupting protein interactions could be possible, but would require blocking of multiple sites. |
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