Posttranslational regulation of self-renewal capacity: insights from proteome and phosphoproteome analyses of stem cell leukemia.
We recently generated 2 phenotypically similar Hoxa9+Meis1 overexpressing acute myeloid leukemias that differ by their in vivo biologic behavior. The first leukemia, named FLA2, shows a high frequency of leukemia stem cells (LSCs; 1 in 1.4 cells), whereas the second, FLB1, is more typical with a frequency of LSCs in the range of 1 per several hundred cells. To gain insights into possible mechanisms that determine LSC self-renewal, we profiled and compared the abundance of nuclear and cytoplasmic proteins and phosphoproteins from these leukemias using quantitative proteomics. These analyses revealed differences in proteins associated with stem cell fate, including a hyperactive p38 MAP kinase in FLB1 and a differentially localized Polycomb group protein Ezh2, which is mostly nuclear in FLA2 and predominantly cytoplasmic in FLB1. Together, these newly documented proteomes and phosphoproteomes represent a unique resource with more than 440 differentially expressed proteins and 11 543 unique phosphopeptides, of which 80% are novel and 7% preferentially phosphorylated in the stem cell-enriched leukemia.
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada.
Matthias
M
Trost
Martin
M
Sauvageau
Olivier
O
Hérault
Paul
P
Deleris
Christelle
C
Pomiès
Jalila
J
Chagraoui
Nadine
N
Mayotte
Sylvain
S
Meloche
Guy
G
Sauvageau
Pierre
P
Thibault
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D004789:Enzyme Activation; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000032:analysis* / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism
D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D020543:Proteome; D012097:Repressor Proteins; D014157:Transcription Factors; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D048051:p38 Mitogen-Activated Protein Kinases