Published online before print June 12, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0206112

Received for publication February 23, 2006.
Revised March 20, 2006.
Accepted for publication March 23, 2006.

Article

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 , and Richard J. D’Andrea ^*@

*Haematology and Oncology Program, Child Health Research Institute, North Adelaide, South Australia; The Queen Elizabeth Hospital, Woodville, South Australia; Departments of Paediatrics and **Medicine and School of Mathematical Sciences, University of Adelaide, South Australia; ^¶The Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Sciences, Adelaide, South Australia; ^||The Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Cancer Biology Program, Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

^@ To whom correspondence should be addressed. E-mail: Richard.dandrea{at}adelaide.edu.au.

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 time-course 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 (C/EBP) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBP mutations.

Key Words: myeloid • transcription factor • myeloid leukemia • microarray • gene expression

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