Genetic regulators of myelopoiesis and leukemic signaling identified by gene profiling and linear modeling

Anna L. Brown, Christopher R. Wilkinson, Scott R. Waterman, Chung H. Kok, Diana G. Salerno, Sonya M. Diakiw, Brenton Reynolds, Hamish S. Scott, Anna Tsykin, Gary F. Glonek, Gregory J. Goodall, Patty J. Solomon, Thomas J. Gonda, Richard J. D'Andrea

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Mechanisms controlling the balance between proliferation and self-renewal versus growth suppression and differentiation during normal and leukemic myelopoiesis are not understood. We have used the bi-potent FDB1 myeloid cell line model, which is responsive to myelopoietic cytokines and activated mutants of the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, having differential signaling and leukemogenic activity. This model is suited to large-scale gene-profiling, and we have used a factorial timecourse design to generate a substantial and powerful data set. Linear modeling was used to identify gene-expression changes associated with continued proliferation, differentiation, or leukemic receptor signaling. We focused on the changing transcription factor profile, defined a set of novel genes with potential to regulate myeloid growth and differentiation, and demonstrated that the FDB1 cell line model is responsive to forced expression of oncogenes identified in this study. We also identified gene-expression changes associated specifically with the leukemic GM-CSF receptor mutant, V449E. Signaling from this receptor mutant down-regulates CCAAT/enhancer-binding protein α (C/EBPα) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBPα mutations.

Original languageEnglish
Pages (from-to)433-447
Number of pages15
JournalJournal of Leukocyte Biology
Volume80
Issue number2
DOIs
Publication statusPublished - 1 Aug 2006

Keywords

  • Gene expression
  • Microarray
  • Myeloid
  • Myeloid leukemia
  • Transcription factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

Brown, A. L., Wilkinson, C. R., Waterman, S. R., Kok, C. H., Salerno, D. G., Diakiw, S. M., ... D'Andrea, R. J. (2006). Genetic regulators of myelopoiesis and leukemic signaling identified by gene profiling and linear modeling. Journal of Leukocyte Biology, 80(2), 433-447. https://doi.org/10.1189/jlb.0206112