IL-3 and oncogenic Abl regulate the myeloblast transcriptome by altering mRNA stability.
The growth factor interleukin-3 (IL-3) promotes the survival and growth of multipotent hematopoietic progenitors and stimulates myelopoiesis. It has also been reported to oppose terminal granulopoiesis and to support leukemic cell growth through autocrine or paracrine mechanisms. The degree to which IL-3 acts at the posttranscriptional level is largely unknown. We have conducted global mRNA decay profiling and bioinformatic analyses in 32Dcl3 myeloblasts indicating that IL-3 caused immediate early stabilization of hundreds of transcripts in pathways relevant to myeloblast function. Stabilized transcripts were enriched for AU-Response elements (AREs), and an ARE-containing domain from the interleukin-6 (IL-6) 3'-UTR rendered a heterologous gene responsive to IL-3-mediated transcript stabilization. Many IL-3-stabilized transcripts had been associated with leukemic transformation. Deregulated Abl kinase shared with IL-3 the ability to delay turnover of transcripts involved in proliferation or differentiation blockade, relying, in part, on signaling through the Mek/Erk pathway. These findings support a model of IL-3 action through mRNA stability control and suggest that aberrant stabilization of an mRNA network linked to IL-3 contributes to leukemic cell growth.
Ernst
Jason
J
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Boston, Massachusetts, USA.
Ghanem
Louis
L
Bar-Joseph
Ziv
Z
McNamara
Michael
M
Brown
Jason
J
Steinman
Richard A
RA
D020816:Amino Acid Motifs; D000818:Animals; D019295:Computational Biology / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D042381:Granulocyte Precursor Cells / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000235:genetics*; D020218:Response Elements
D007377:Interleukin-3; D016315:Proto-Oncogene Proteins c-abl; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1