Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acute Disease
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism
-
Animals
-
Blotting, Western
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism*
-
Cell Transformation, Neoplastic / genetics
-
Cells, Cultured
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Dishevelled Proteins
-
Female
-
Glycogen Synthase Kinase 3 / genetics
-
Glycogen Synthase Kinase 3 / metabolism
-
HEK293 Cells
-
Hematopoietic Stem Cells / metabolism
-
Histone-Lysine N-Methyltransferase
-
Humans
-
Leukemia, Myeloid / genetics
-
Leukemia, Myeloid / metabolism
-
Leukemia, Myeloid / pathology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid-Lymphoid Leukemia Protein / genetics
-
Myeloid-Lymphoid Leukemia Protein / metabolism*
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Oncogene Fusion
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism*
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism
-
Proto-Oncogene Proteins
-
RNA Interference
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
rac GTP-Binding Proteins / genetics
-
rac GTP-Binding Proteins / metabolism*
Substances
-
Adaptor Proteins, Signal Transducing
-
Carrier Proteins
-
DNA-Binding Proteins
-
Dishevelled Proteins
-
Frat1 protein, mouse
-
Frat2 protein, mouse
-
Mllt1 protein, mouse
-
Mllt3 protein, mouse
-
Neoplasm Proteins
-
Nuclear Proteins
-
Oncogene Proteins, Fusion
-
Phosphoproteins
-
Proto-Oncogene Proteins
-
Transcription Factors
-
Myeloid-Lymphoid Leukemia Protein
-
Histone-Lysine N-Methyltransferase
-
Kmt2a protein, mouse
-
Glycogen Synthase Kinase 3
-
rac GTP-Binding Proteins