Frat2 mediates the oncogenic activation of Rac by MLL fusions.
Mixed lineage leukemia (MLL) fusion genes arise from chromosomal translocations and induce acute myeloid leukemia through a mechanism involving transcriptional deregulation of differentiation and self-renewal programs. Progression of MLL-rearranged acute myeloid leukemia is associated with increased activation of Rac GTPases. Here, we demonstrate that MLL fusion oncogenes maintain leukemia-associated Rac activity by regulating Frat gene expression, specifically Frat2. Modulation of FRAT2 leads to concomitant changes in Rac activity, and transformation of Frat knockout hematopoietic progenitor cells by MLL fusions results in leukemias displaying reduced Rac activation and increased sensitivity to chemotherapeutic drugs. FRAT2 activates Rac through a signaling mechanism that requires glycogen synthase kinase 3 and DVL. Disruption of this pathway abrogates the leukemogenic activity of MLL fusions. This suggests a rationale for the paradoxical requirement of canonical Wnt signaling and glycogen synthase kinase 3 activity for MLL fusion oncogenicity and identifies novel therapeutic targets for this disease.
Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, United Kingdom.
Vanessa
V
Walf-Vorderwülbecke
Jasper
J
de Boer
Sarah J
SJ
Horton
Renée
R
van Amerongen
Natalie
N
Proost
Anton
A
Berns
Owen
O
Williams
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; C491818:Frat1 protein, mouse; C488487:Frat2 protein, mouse; C493508:Mllt1 protein, mouse; C489902:Mllt3 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D038362:Glycogen Synthase Kinase 3; D020744:rac GTP-Binding Proteins