Genetic regulators of myelopoiesis and leukemic signaling identified by gene profiling and linear modeling.
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 alpha (C/EBPalpha) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBPalpha mutations.
Brown
Anna L
AL
Haematology and Oncology Program, Child Health Research Institute, North Adelaide, South Australia.
Wilkinson
Christopher R
CR
Waterman
Scott R
SR
Kok
Chung H
CH
Salerno
Diana G
DG
Diakiw
Sonya M
SM
Reynolds
Brenton
B
Scott
Hamish S
HS
Tsykin
Anna
A
Glonek
Gary F
GF
Goodall
Gregory J
GJ
Solomon
Patty J
PJ
Gonda
Thomas J
TJ
D'Andrea
Richard J
RJ
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family; D038042:Myelopoiesis / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D015398:Signal Transduction
D022782:CCAAT-Enhancer-Binding Protein-beta; D017978:Receptors, Growth Factor