A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice

Kara J. Johnson, Ian J. Griswold, Thomas O'Hare, Amie S. Corbin, Marc Loriaux, Michael W. Deininger, Brian Druker

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0007439
JournalPLoS One
Volume4
Issue number10
DOIs
StatePublished - 2009

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leukemia
binding sites
Leukemia
Binding Sites
myeloid leukemia
mutants
phosphotransferases (kinases)
mice
Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Proteins
proteins
interleukin-3
multiprotein complexes
cells
mitogen-activated protein kinase
Phosphorylation
Interleukin-3
Mitogen-Activated Protein Kinase Kinases
tyrosine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice. / Johnson, Kara J.; Griswold, Ian J.; O'Hare, Thomas; Corbin, Amie S.; Loriaux, Marc; Deininger, Michael W.; Druker, Brian.

In: PLoS One, Vol. 4, No. 10, e0007439, 2009.

Research output: Contribution to journalArticle

Johnson, Kara J. ; Griswold, Ian J. ; O'Hare, Thomas ; Corbin, Amie S. ; Loriaux, Marc ; Deininger, Michael W. ; Druker, Brian. / A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice. In: PLoS One. 2009 ; Vol. 4, No. 10.
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