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

Brown, AL; Wilkinson, CR; Waterman, SR; Kok, CH; Salerno, DG; Diakiw, SM; Reynolds, B; Scott, HS; Tsykin, A; Glonek, GF; Goodall, GJ; Solomon, PJ; Gonda, TJ; D&#39;Andrea, RJ

Author(s): Brown, AL; Wilkinson, CR; Waterman, SR; Kok, CH; Salerno, DG; Diakiw, SM; Reynolds, B; Scott, HS; Tsykin, A; Glonek, GF; Goodall, GJ; Solomon, PJ; Gonda, TJ; D'Andrea, RJ;
Details: Publication Year 2006-08,Volume 80,Issue #2,Page 433-447
Journal Title: JOURNAL OF LEUKOCYTE BIOLOGY
Publication Type: Journal Article
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 downregulates CCAAT/enhancer-binding protein ox (C/EBP alpha) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBP alpha mutations. J. Leukoc. Biol. 80: 433-447; 2006.
Publisher: FEDERATION AMER SOC EXP BIOL
Keywords: ACUTE MYELOID-LEUKEMIA; COMMON BETA-SUBUNIT; HEMATOPOIETIC PROGENITOR CELLS; ACUTE MYELOGENOUS LEUKEMIA; COLONY-STIMULATING FACTOR; DNA MICROARRAY ANALYSIS; TRANSCRIPTION FACTORS; EXPRESSION PROFILES; C/EBP-ALPHA; GM-CSF
Publisher's Version: https://doi.org/10.1189/jlb.0206112
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2006-08-01 12:00:00