High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia

Marc M. Loriaux, Ross L. Levine, Jeffrey W. Tyner, Stefan Fröhling, Claudia Scholl, Eric P. Stoffregen, Gerlinde Wernig, Heidi Erickson, Christopher A. Eide, Roland Berger, Olivier A. Bernard, James D. Griffin, Richard M. Stone, Benjamin Lee, Matthew Meyerson, Michael C. Heinrich, Michael W. Deininger, D. Gary Gilliland, Brian J. Druker

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

To determine whether aberrantly activated tyrosine kinases other than FLT3 and c-KIT contribute to acute myeloid leukemia (AML) pathogenesis, we used high-throughput (HT) DNA sequence analysis to screen exons encoding the activation loop and juxtamembrane domains of 85 tyrosine kinase genes in 188 AML patients without FLT3 or c-KIT mutations. The screen identified 30 nonsynonymous sequence variations in 22 different kinases not previously reported in singlenucleotide polymorphism (SNP) databases. These included a novel FLT3 activating allele and a previously described activating mutation in MET (METT1010I). The majority of novel sequence variants were stably expressed in factor-dependent Ba/F3 cells. Apart from one FLT3 allele, none of the novel variants showed constitutive phosphorylation by immunoblot analysis and none transformed Ba/F3 cells to factorindependent growth. These findings indicate the majority of these alleles are not potent tyrosine kinase activators in this cellular context and that a significant proportion of nonsynonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Although some sequence variants may represent SNPs, these data are consistent with recent reports that a significant fraction of such sequence variants are "passenger" rather than "driver" alleles and underscore the importance of functional assessment of candidate disease alleles.

Original languageEnglish (US)
Pages (from-to)4788-4796
Number of pages9
JournalBlood
Volume111
Issue number9
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Loriaux, M. M., Levine, R. L., Tyner, J. W., Fröhling, S., Scholl, C., Stoffregen, E. P., Wernig, G., Erickson, H., Eide, C. A., Berger, R., Bernard, O. A., Griffin, J. D., Stone, R. M., Lee, B., Meyerson, M., Heinrich, M. C., Deininger, M. W., Gilliland, D. G., & Druker, B. J. (2008). High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood, 111(9), 4788-4796. https://doi.org/10.1182/blood-2007-07-101394